Hypertrophic Cardiomyopathy 3

Genetic MONDO:0007267 Pathograph 19 Show in embeddings browser Hypertrophic Cardiomyopathy Genetic Disorder

Hypertrophic cardiomyopathy 3 (CMH3) is the TPM1-related form of familial hypertrophic cardiomyopathy. TPM1 encodes alpha-tropomyosin, the elongated coiled-coil dimer that lies in the groove of the actin thin filament and, together with the troponin complex, gates myosin access to actin across the blocked, closed, and open regulatory states of the cardiac sarcomere. CMH3 was one of the two founding observations that established hypertrophic cardiomyopathy as a disease of the sarcomere: missense variants at the chromosome 15q locus (Asp175Asn, Glu180Gly) were shown in 1994 to cosegregate with familial hypertrophic cardiomyopathy. Because tropomyosin's job is inhibitory, the recurring molecular consequence of HCM-associated TPM1 variants is a failure to keep crossbridges switched off: molecular-dynamics, in vitro motility, and engineered-heart-tissue studies of S215L, E192K, D219V, and E62Q converge on destabilization of the inhibited regulatory state, higher myofilament calcium sensitivity or residual actomyosin activity at low calcium, hypercontractility, and impaired relaxation, with induction of a hypertrophic gene program downstream. The clinical picture is that of hypertrophic cardiomyopathy generally - unexplained left ventricular hypertrophy, myocyte hypertrophy with disarray and replacement fibrosis on histology, diastolic dysfunction, arrhythmia, and a risk of sudden cardiac death - but TPM1 is a minority cause, historically about 3% of familial cases, and outcome is strongly variant-dependent: the founder variant p.Arg21Leu shows late-onset, incomplete penetrance and generally favourable prognosis, while other alleles have been reported in families ascertained through sudden cardiac death. TPM1 is also an allelic cause of dilated, restrictive, and noncompaction cardiomyopathy, and disentangling which molecular consequence steers a carrier toward the hypertrophic rather than the dilated phenotype is an active research question.

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2
Inheritance
9
Pathophys.
14
Phenotypes
3
Hypotheses
4
Gaps
19
Pathograph
2
Genes
3
Medical Actions
3
Differentials
4
Models
3
References
1
Deep Research
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Classifications

Harrison's Part
CARDIOVASCULAR GENETICS ENVIRONMENT DISEASE
👪

Inheritance

2
Autosomal Dominant HP:0000006
CMH3 is transmitted as an autosomal dominant trait, and the TPM1-HCM gene-disease relationship has been classified by ClinGen's Hereditary Cardiovascular Disease Gene Curation Expert Panel as Definitive with autosomal dominant inheritance. Penetrance is incomplete and age-dependent, and both severity and age at diagnosis are variant- and sex-dependent.
Autosomal dominant inheritance Penetrance: INCOMPLETE
Show evidence (3 references)
CGGV:assertion_32e7ed58-ee49-4719-b48e-7fad58012319-2023-12-18T170000.000Z SUPPORT Other
"TPM1 | HGNC:12010 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Definitive"
ClinGen's Hereditary Cardiovascular Disease GCEP records autosomal dominant inheritance for the TPM1-hypertrophic cardiomyopathy relationship with Definitive clinical validity.
PMID:25607779 SUPPORT Human Clinical
"Of these, one mutant, S215L, was identified in two unrelated HCM cases"
Documents identification of the S215L allele in unrelated HCM probands in a family study reporting autosomal dominant cosegregation.
PMID:33642254 SUPPORT Human Clinical
"The cumulative probability of diagnosis in carriers was 50% at the age of 50 years for males, and was 25% in female carriers."
Quantifies age-dependent, sex-modified incomplete penetrance in the largest single-variant TPM1 HCM pedigree series.
Autosomal Recessive (Rare Homozygous) HP:0000007
Homozygous TPM1 genotypes are rare but reported, including a homozygous exon 1 missense variant in a non-consanguineous family with paediatric HCM, and 6% of carriers in the p.Arg21Leu founder series were homozygous. Homozygosity is a dose effect on the same dominant allele rather than a mechanistically distinct recessive disease.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:32744700 SUPPORT Human Clinical
"to our knowledge, this is the first report of the homozygous missense variation p.Gly3Arg in TPM1 associated with familial autosomal recessive pediatric HCM and PDA."
Reports a homozygous TPM1 genotype segregating with paediatric hypertrophic cardiomyopathy, establishing that biallelic TPM1 disease occurs.
PMID:33642254 SUPPORT Human Clinical
"Six percent of carriers were homozygous and 18% had an additional variant."
Documents that homozygosity for a TPM1 HCM allele occurs at appreciable frequency in a founder population, alongside frequent additional sarcomere-gene variants.
◈

Mechanistic Hypotheses

3
Loss of tropomyosin-mediated crossbridge inhibition
tpm1_loss_of_crossbridge_inhibition CANONICAL
Evidence balance 2 support
The canonical model of CMH3 is that HCM-associated TPM1 variants degrade tropomyosin's inhibitory function on the thin filament. Molecular-dynamics simulations show mutant tropomyosin is more flexible and its blocked/closed positioning on actin is destabilized; in vitro motility assays show higher calcium sensitivity of filament sliding and failure to inhibit sliding at low calcium; engineered heart tissues built from the same variants are hypercontractile with impaired relaxation and induce hypertrophic gene markers. Under this model the proximate lesion is excess residual actomyosin interaction rather than a loss of force-generating capacity.
Pathograph links
Alpha-Tropomyosin Thin Filament Regulatory Defect -> Loss of Crossbridge Inhibition and Increased Myofilament Calcium Sensitivity DIRECT
Loss of Crossbridge Inhibition and Increased Myofilament Calcium Sensitivity -> Cardiomyocyte Hypercontractility and Impaired Relaxation DIRECT
Cardiomyocyte Hypercontractility and Impaired Relaxation -> Cardiomyocyte Hypertrophy with Myofiber Disarray and Interstitial Fibrosis DIRECT
Show evidence (2 references)
PMID:36896133 SUPPORT In Vitro
"These simulations and experiments support the classification of S215L as a pathogenic mutation and support the hypothesis that an inability to adequately inhibit actomyosin interactions is the mechanism whereby thin-filament mutations cause HCM."
States the loss-of-inhibition hypothesis explicitly as the conclusion of a combined simulation, motility-assay, and engineered-heart-tissue study of a TPM1 HCM variant.
PMID:34319370 SUPPORT In Vitro
"These results suggest that the TPM1 E192K mutation triggers cardiomyocyte hypertrophy by permitting excess residual crossbridge activity."
Independent confirmation of the same mechanism in a second TPM1 variant, using patient-derived engineered heart tissue.
Myofilament calcium buffering as the initiator of hypertrophic signaling
tpm1_calcium_buffering_signaling ALTERNATIVE
Evidence balance 1 support
A complementary account places the primary lesion one step downstream of the regulatory defect: because mutant thin filaments bind calcium more avidly, myofilament calcium buffering rises, diastolic calcium increases, reuptake slows, and calcium-dependent signaling through CaMKII, calcineurin/NFAT, and ERK is chronically engaged - providing the transcriptional drive for hypertrophy independent of the mechanical effect. The two accounts are not exclusive; they differ in what they nominate as the rate-limiting step and therefore in what a therapy should target.
Pathograph links
Alpha-Tropomyosin Thin Filament Regulatory Defect -> Increased Myofilament Calcium Buffering and Calcium-Dependent Signaling DIRECT
Increased Myofilament Calcium Buffering and Calcium-Dependent Signaling -> Cardiomyocyte Hypertrophy with Myofiber Disarray and Interstitial Fibrosis DIRECT
Show evidence (1 reference)
PMID:29760186 SUPPORT In Vitro
"Altered myofilament Ca2+ buffering is the primary initiator of signaling cascades, indicating that directly targeting myofilament Ca2+ sensitivity provides an attractive therapeutic approach in HCM."
States the alternative primacy claim. The study expressed the TPM1 HCM variant D175N (alongside troponin variants) in isolated cardiomyocytes, so it speaks directly to the CMH3 thin-filament lesion.
Variant-specific molecular divergence between hypertrophic and dilated TPM1 phenotypes
tpm1_variant_specific_phenotype_divergence EMERGING
Evidence balance 2 support
TPM1 variants cause hypertrophic, dilated, restrictive, and noncompaction cardiomyopathy, and an emerging body of work proposes that the divergence is set by which physical property of tropomyosin the substitution perturbs. Paired analysis of E62Q (HCM) and E54K (DCM) attributes the hypertrophic phenotype to reduced molecular stiffness with a shift toward the closed regulatory state, and the dilated phenotype to a long-range allosteric change in troponin I mobile-domain binding. Whether this generalizes across the TPM1 allelic series, and how it interacts with modifier genotype and sex, is not settled.
Pathograph links
Alpha-Tropomyosin Thin Filament Regulatory Defect -> Divergent Non-Hypertrophic Remodeling Phenotypes INDIRECT UNKNOWN INTERMEDIATES Allele-dependent branch: some TPM1 substitutions produce dilated, restrictive, or noncompaction remodeling instead of hypertrophy, and the determinants are not established.
Show evidence (2 references)
PMID:39436707 SUPPORT Computational
"Our objective was to develop a mechanistic explanation of diverging phenotypes in two TPM1 mutations, E62Q (HCM) and E54K (DCM)."
Frames the hypothesis. Evidence source is COMPUTATIONAL because the mechanistic explanation is delivered by simulation constrained by stem-cell-derived cardiomyocyte data.
PMID:31643006 SUPPORT In Vitro
"Here, we found that the studied Tpm mutations differently affected the duration: the D175N mutation reduced it compared to WT Tpm, while the E180G mutation increased it."
Shows that even two hypertrophic TPM1 alleles diverge at the single-molecule level, supporting variant specificity. PARTIAL because it does not itself connect the molecular divergence to a clinical phenotype.
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Discussions and Knowledge Gaps

4
Is the rate-limiting step in CMH3 the mechanical loss of crossbridge inhibition, or the increase in myofilament calcium buffering that drives calcium-dependent hypertrophic signaling - and does the answer differ by allele?
KNOWLEDGE GAP OPEN tpm1_which_molecular_step_is_rate_limiting
Attached to
pathophysiology#Loss of Crossbridge Inhibition and Increased Myofilament Calcium Sensitivity pathophysiology#Increased Myofilament Calcium Buffering and Calcium-Dependent Signaling
The two hypothesis groups curated here nominate different rate-limiting steps and imply different therapeutic targets: myosin inhibition if the mechanical arm dominates, calcium-desensitisation if the signaling arm does. The supporting studies use different alleles in different systems (S215L, E192K, and E62Q in engineered heart tissue; D175N in isolated cardiomyocytes), so no single system has tested both arms against each other for the same variant. Until that is done the pathograph must carry both arms rather than assert a single canonical chain.
Show evidence (2 references)
PMID:29760186 SUPPORT In Vitro
"Altered myofilament Ca2+ buffering is the primary initiator of signaling cascades, indicating that directly targeting myofilament Ca2+ sensitivity provides an attractive therapeutic approach in HCM."
One side of the open question, asserting calcium buffering as primary.
PMID:36896133 SUPPORT In Vitro
"These data form a mechanistic description of TPM1 S215L pathogenicity that starts with disruption of the mechanical and regulatory properties of tropomyosin, leading thereafter to hypercontractility and finally induction of a hypertrophic phenotype."
The other side, placing the mechanical/regulatory disruption first in the causal order.
What determines whether a given TPM1 substitution produces hypertrophic, dilated, restrictive, or noncompaction cardiomyopathy, and can that mapping be predicted from the residue's structural role well enough to guide variant interpretation?
KNOWLEDGE GAP OPEN tpm1_allele_to_phenotype_map
Attached to
pathophysiology#Divergent Non-Hypertrophic Remodeling Phenotypes
TPM1 is a single small gene with at least four distinct cardiomyopathy outputs, and within a single family the same variant can produce diastolic dysfunction in one relative and overt HCM in another, while compound heterozygosity produced restrictive disease in a child. One paired study offers a molecular explanation for the hypertrophic-versus-dilated split, but it covers two variants. Without a systematic allele-to-mechanism-to-phenotype map, a novel TPM1 missense finding cannot be assigned to CMH3 rather than to its allelic siblings on mechanistic grounds, and the therapeutic direction (myosin inhibition versus activation) is not determinable from the genotype.
Show evidence (2 references)
PMID:32882290 SUPPORT Human Clinical
"We identified a large family with DCM carrying a recently identified TPM1 gene variant (T201M) and a child with RCM with compound heterozygote TPM1 variants (E62Q and M281T) whose family members carrying single variants show diastolic dysfunction and HCM."
Illustrates the within-gene and within-family phenotypic divergence that the gap concerns.
PMID:32217077 SUPPORT Other
"Several mutation-mediated disease mechanisms have been identified, with proof for gene- and mutation-specific cellular perturbations."
Confirms that mutation-specific mechanism is an established phenomenon in HCM, making an allele-resolved map a realistic rather than speculative goal.
Do engineered heart tissues and hiPSC-cardiomyocytes carrying TPM1 variants faithfully model adult human CMH3, given that they are immature, lack the fibrotic and neurohormonal context, and in several studies overexpress the variant rather than carry it at endogenous dose?
HUMAN MODEL MISMATCH OPEN tpm1_hcm_human_model_fidelity
Attached to
pathophysiology#Cardiomyocyte Hypercontractility and Impaired Relaxation
Almost all of the mechanistic evidence for CMH3 curated here comes from engineered tissue, hiPSC-cardiomyocytes, reconstituted filaments, or simulation - the human clinical literature supplies genotype-phenotype correlation but essentially no mechanism. These systems reproduce hypercontractility and diastolic dysfunction convincingly, but they cannot reproduce the fibrosis, disarray, and neurohormonal remodeling that dominate the clinical disease, and overexpression studies replaced a substantial fraction of endogenous protein. The direction of a reported effect can even invert between systems: one variant panel reported reduced calcium-transient amplitude in overexpressing cardiomyocytes, whereas the buffering study reported increased diastolic calcium. This is an open question of translational validity rather than an absence of evidence.
Show evidence (5 references)
PMID:32882290 SUPPORT In Vitro
"To define toxic threshold levels, we performed dose-dependent transfection of TPM1 variants."
Documents that the model relies on transfected overexpression at experimenter-set dose, the specific fidelity concern raised here.
PMID:32217077 SUPPORT Other
"The pros and cons of these experimental models for studying mutation-specific HCM pathology and therapies will be outlined."
A dedicated review of exactly this model-fidelity question for HCM, confirming it is a recognized open issue rather than a curation artefact.
PMID:10900175 SUPPORT In Vitro
"The results using human cardiac regulatory proteins reveal different effects of the HCM mutations in tropomyosin compared to studies using heterologous systems."
The sharpest statement of the fidelity problem for this specific gene: for TPM1, non-human or heterologous systems give qualitatively different answers, so a mechanistic result is only as trustworthy as its protein isoform context.
+ 2 more references
What is the true arrhythmic risk in TPM1 hypertrophic cardiomyopathy, and do the established HCM sudden-death risk models calibrate correctly in thin-filament disease?
KNOWLEDGE GAP OPEN tpm1_arrhythmic_risk_and_risk_scd_calibration
Attached to
phenotypes#Sudden Cardiac Death phenotypes#Non-Sustained Ventricular Tachycardia
The literature points in two directions at once, and the disagreement is not resolvable from the published evidence. Narrative reviews of thin-filament cardiomyopathy describe a high sudden-death risk marked by family history, non-sustained ventricular arrhythmia and abnormal exercise blood-pressure response. The one prospective thin-filament cohort with nearly five years of follow-up reports the opposite: no malignant arrhythmic event occurred in any thin-filament patient, and its authors state directly that the higher-risk claim is controversial between studies and depends on age of onset and genotype within individual families. Both readings cannot be right for the same population. The practical consequence is a calibration question rather than an academic one. The conventional sudden-death risk models were derived on cohorts dominated by thick-filament genotypes, and the same cohort study found thin-filament patients had milder hypertrophy - the dominant input to those models - while progressing to advanced heart failure roughly five times faster. A model driven by wall thickness may therefore systematically under-call risk in a genotype whose danger is weighted toward heart failure rather than toward hypertrophy, or may correctly identify a genuinely lower arrhythmic risk. Nothing in the current evidence distinguishes those. TPM1 specifically cannot settle it: it accounted for 9 of 285 carriers in the largest penetrance cohort and a minority of the 15 thin-filament patients in the outcome cohort.
Proposed experiments
External validation of HCM sudden-death risk models in thin-filament genotypes
tpm1_thin_filament_risk_scd_calibration
Pool thin-filament HCM patients across the existing genotyped registries and assess calibration of the established risk models - observed versus predicted event rates, stratified by thin-filament versus thick-filament genotype. The cohorts required already exist and are genotyped; what is missing is the stratified calibration analysis. A systematic under-prediction in thin-filament carriers would justify a genotype term in risk assessment, and a correct calibration would settle the controversy in the other direction.
Show evidence (3 references)
DOI:10.3390/jcm14030866 SUPPORT Human Clinical
"None of the thin-filament HCM patients experienced malignant arrhythmic events."
The prospective observation that contradicts the high-arrhythmic-risk framing, in the only thin-filament cohort with follow-up.
DOI:10.3390/jcm14030866 SUPPORT Human Clinical
"Data on a higher risk of malignant arrhythmias in thin-filament HCM remain controversial between studies and rather depend on the age of onset and genotype in each particular family."
The authors state the controversy explicitly, which is what makes this a knowledge gap rather than a settled contradiction to be resolved in favour of one side.
DOI:10.3390/jcm14030866 SUPPORT Human Clinical
"showed more rapid progression to advanced heart failure (HR = 5.6, p = 0.018)"
The quantified heart-failure hazard that makes the risk profile in this class weighted toward heart failure rather than arrhythmia, which is the substance of the calibration concern.
⚙

Pathophysiology

9
Alpha-Tropomyosin Thin Filament Regulatory Defect
TPM1 encodes alpha-tropomyosin, a rod-shaped coiled-coil dimer that polymerises head-to-tail along the actin thin filament and, in concert with the troponin complex, occupies the blocked, closed, or open azimuthal position that determines whether myosin can engage actin. Disease-associated missense substitutions are scattered along the molecule - in the N-terminal overlap/troponin T binding region (Arg21Leu, Gly3Arg, Glu62Gln, Gln68Arg), in the central period 4/5 region that contacts actin (Asp175Asn, Glu180Gly, Glu192Lys), and in the C-terminal region (Ser215Leu, Asp219Val, Asp254Gly) - and act by altering tropomyosin flexibility, its azimuthal positioning on actin, or its interactions with troponin, rather than by abolishing the protein. This is the primary cardiomyocyte insult of CMH3.
Loss of tropomyosin-mediated crossbridge inhibition Myofilament calcium buffering as the initiator of hypertrophic signaling Variant-specific molecular divergence between hypertrophic and dilated TPM1 phenotypes
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
TPM1 hgnc:12010 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TPM1 (hgnc:12010). hgnc:12010 is a gene from the HUGO Gene Nomenclature Committee.
Regulation of muscle contraction GO:0006937 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Regulation of muscle contraction (GO:0006937). GO:0006937 is a biological process from the Gene Ontology. ⚠ ABNORMAL
actin filament binding GO:0051015 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves abnormal actin filament binding (GO:0051015). GO:0051015 is a molecular function from the Gene Ontology. ⚠ ABNORMAL structural constituent of muscle GO:0008307 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves abnormal structural constituent of muscle (GO:0008307). GO:0008307 is a molecular function from the Gene Ontology. ⚠ ABNORMAL
sarcomere GO:0030017 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves sarcomere (GO:0030017). GO:0030017 is a cellular component from the Gene Ontology. thin filament GO:0005865 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves thin filament, annotated with striated muscle thin filament (GO:0005865). GO:0005865 is a cellular component from the Gene Ontology.
Myocardium UBERON:0002349 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Myocardium (UBERON:0002349). UBERON:0002349 is an anatomical location from the Uberon multi-species anatomy ontology.
Experimental models
Alpha-TM180 transgenic mouse (TPM1 Glu180Gly) OTHER
Downstream
Loss of Crossbridge Inhibition and Increased Myofilament Calcium Sensitivity Loss of tropomyosin-mediated crossbridge inhibition
Increased Myofilament Calcium Buffering and Calcium-Dependent Signaling Myofilament calcium buffering as the initiator of hypertrophic signaling
Divergent Non-Hypertrophic Remodeling Phenotypes Allele-dependent branch: some TPM1 substitutions produce dilated, restrictive, or noncompaction remodeling instead of hypertrophy, and the determinants are not established. Variant-specific molecular divergence between hypertrophic and dilated TPM1 phenotypes
Show evidence (5 references)
PMID:8205619 SUPPORT Human Clinical
"We demonstrate that missense mutations (Asp175Asn; Glu180Gly) in the alpha-tropomyosin gene cause familial hypertrophic cardiomyopathy (FHC) linked to chromosome 15q2."
The founding CMH3 observation: alpha-tropomyosin missense variants at the 15q locus cause familial hypertrophic cardiomyopathy.
PMID:8205619 SUPPORT Human Clinical
"Because alpha-tropomyosin and cardiac troponin T as well as beta myosin heavy chain mutations cause the same phenotype, we conclude that FHC is a disease of the sarcomere."
Establishes that the TPM1 lesion belongs to the same sarcomeric-protein class as the thick-filament causes, which is why this node conforms to the generic primary-cardiomyocyte-insult node of the cardiomyopathy module.
PMID:38223010 SUPPORT Human Clinical
"Mutations in TPM1 are known to cause hypertrophic cardiomyopathy, dilated cardiomyopathy and left ventricular non-compaction."
Documents that the same gene underlies several cardiomyopathy phenotypes, the allelic-series context in which CMH3 sits.
+ 2 more references
Loss of Crossbridge Inhibition and Increased Myofilament Calcium Sensitivity
Mutant alpha-tropomyosin is more flexible and sits less stably in the inhibitory (blocked/closed) position on actin, so the thin filament fails to keep myosin switched off. The measurable consequences are a left-shift in the calcium dependence of filament sliding, residual actomyosin activity at low calcium, and loss of the normal inhibition of sliding in relaxing conditions. Different alleles reach this end state by different routes - S215L and D219V principally by destabilizing the blocked state, E192K by permitting residual crossbridge activity even while overall calcium sensitivity falls - which is why calcium sensitivity alone is an incomplete description of the lesion.
Loss of tropomyosin-mediated crossbridge inhibition
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Regulation of muscle filament sliding GO:0032971 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Regulation of muscle filament sliding (GO:0032971). GO:0032971 is a biological process from the Gene Ontology. ⚠ ABNORMAL Muscle filament sliding GO:0030049 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Muscle filament sliding (GO:0030049). GO:0030049 is a biological process from the Gene Ontology. ↑ INCREASED
striated muscle thin filament GO:0005865 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves striated muscle thin filament (GO:0005865). GO:0005865 is a cellular component from the Gene Ontology.
Experimental models
Genetically engineered heart tissue expressing TPM1 S215L IPSC DERIVED MODEL
Downstream
Cardiomyocyte Hypercontractility and Impaired Relaxation Loss of tropomyosin-mediated crossbridge inhibition
Show evidence (7 references)
PMID:36896133 SUPPORT Computational
"Molecular dynamic simulations of tropomyosin on actin suggest that the S215L significantly destabilizes the blocked regulatory state while increasing flexibility of the tropomyosin chain."
Direct structural statement of the regulatory-state destabilization that defines this node. Evidence source is COMPUTATIONAL because the claim comes from molecular-dynamics simulation.
PMID:36896133 SUPPORT In Vitro
"In vitro motility experiments with thin filaments containing TPM1 S215L revealed higher Ca2+ sensitivity compared with wild type."
Experimental confirmation in reconstituted thin filaments that the simulated destabilization translates into increased myofilament calcium sensitivity.
PMID:36613463 SUPPORT In Vitro
"The D219V mutation significantly increased the Ca2+ sensitivity of the sliding velocity of thin filaments over cardiac myosin in an in vitro motility assay and impaired the inhibition of the filament sliding at low Ca2+ concentration."
Independent replication in a second TPM1 HCM allele, and the clearest single statement of the two components of the lesion - increased calcium sensitivity plus failure of inhibition at low calcium.
+ 4 more references
Increased Myofilament Calcium Buffering and Calcium-Dependent Signaling
Because the mutant thin filament binds calcium more tightly, more of the cytosolic calcium transient is sequestered on the myofilaments. Diastolic calcium rises and reuptake slows; compensatory changes in sodium/calcium exchange, SERCA2 activity, and ryanodine-receptor leak follow, driven by CaMKII phosphorylation. The altered calcium environment chronically engages the calcineurin/NFAT and ERK pathways that transcriptionally program cardiomyocyte hypertrophy, and also creates a substrate for triggered arrhythmia.
Myofilament calcium buffering as the initiator of hypertrophic signaling
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Intracellular calcium ion homeostasis GO:0006874 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Intracellular calcium ion homeostasis (GO:0006874). GO:0006874 is a biological process from the Gene Ontology. ⚠ ABNORMAL Calcineurin-NFAT signaling cascade GO:0033173 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Calcineurin-NFAT signaling cascade (GO:0033173). GO:0033173 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Cardiomyocyte Hypertrophy with Myofiber Disarray and Interstitial Fibrosis Myofilament calcium buffering as the initiator of hypertrophic signaling
Arrhythmogenic Substrate and Sudden Cardiac Death Raised diastolic calcium, CaMKII-driven ryanodine-receptor leak, and altered repolarization contribute to triggered activity.
Show evidence (4 references)
PMID:29760186 SUPPORT In Vitro
"HCM mutations significantly lowered the Kd of Ca2+ binding, resulting in higher Ca2+ buffering of mutant cardiomyocytes."
Quantifies the buffering change in cardiomyocytes expressing HCM thin-filament variants including the TPM1 allele D175N.
PMID:29760186 SUPPORT In Vitro
"coupled with a significant decrease in basal sarcomere length and slowed relaxation"
Links the buffering change to the diastolic phenotype: in the same sentence the authors report increased diastolic calcium and slowed calcium reuptake, and the quoted clause gives the mechanical consequence - shorter resting sarcomere length and slower relaxation. The quote starts mid-sentence because the preceding clause writes the calcium concentration in square brackets, which the reference validator normalizes away.
PMID:29760186 SUPPORT In Vitro
"Altered Ca2+ homeostasis also increased signaling via both calcineurin/NFAT and extracellular signal-regulated kinase pathways."
Provides the transcriptional link from the calcium abnormality to the hypertrophic program.
+ 1 more reference
Cardiomyocyte Hypercontractility and Impaired Relaxation
At the level of the working myocyte the regulatory defect presents as hypercontractility with a relaxation deficit: three-dimensional engineered heart tissues carrying TPM1 HCM variants generate excess force, relax slowly, and show diastolic dysfunction, together with induction of hypertrophic gene markers and cellular hypertrophy. Patient-derived hiPSC-cardiomyocytes carrying the classic Asp175Asn allele reproduce the cellular phenotype with increased cell size and altered calcium handling and electrophysiology. Hypercontractility is the pathophysiological abnormality that myosin-inhibitor therapy is designed to reverse.
Loss of tropomyosin-mediated crossbridge inhibition
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Cardiac muscle contraction GO:0060048 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Cardiac muscle contraction (GO:0060048). GO:0060048 is a biological process from the Gene Ontology. ↑ INCREASED Relaxation of cardiac muscle GO:0055119 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Relaxation of cardiac muscle (GO:0055119). GO:0055119 is a biological process from the Gene Ontology. ↓ DECREASED
Experimental models
Patient-derived engineered heart tissue expressing TPM1 E192K IPSC DERIVED MODEL
Genetically engineered heart tissue expressing TPM1 S215L IPSC DERIVED MODEL
Patient hiPSC-derived cardiomyocytes carrying TPM1 Asp175Asn IPSC DERIVED MODEL
Downstream
Cardiomyocyte Hypertrophy with Myofiber Disarray and Interstitial Fibrosis Loss of tropomyosin-mediated crossbridge inhibition
Diastolic Dysfunction and Left Ventricular Outflow Tract Obstruction
Show evidence (4 references)
PMID:36896133 SUPPORT In Vitro
"Three-dimensional genetically engineered heart tissues expressing TPM1 S215L exhibited hypercontractility, upregulation of hypertrophic gene markers, and diastolic dysfunction."
Direct tissue-level demonstration of the three components of this node in a TPM1 HCM variant.
PMID:34319370 SUPPORT In Vitro
"These tissues showed disease features similar to those of the patients, including cellular hypertrophy, hypercontractility, and diastolic dysfunction."
Replicates the same triad in patient-derived engineered heart tissue and explicitly ties it to the donors' clinical features.
PMID:27057166 SUPPORT In Vitro
"Both types of HCM-CMs displayed pathological phenotype of HCM but, more importantly, we found differences between CMs carrying either MYBPC3-Gln1061X or TPM1-Asp175Asn gene mutation in their cellular size, Ca(2+) handling, and electrophysiological properties, as well as their gene expression profiles."
Shows that patient hiPSC-cardiomyocytes carrying the founding CMH3 allele reproduce a cellular HCM phenotype, and that it differs in detail from a thick-filament HCM phenotype.
+ 1 more reference
Cardiomyocyte Hypertrophy with Myofiber Disarray and Interstitial Fibrosis
Sustained hypercontractility and calcium-dependent hypertrophic signaling remodel the myocardium into the classic hypertrophic pattern: myocyte hypertrophy, loss of the normal parallel myofibre architecture (disarray), and replacement/interstitial fibrosis, producing wall thickening with a small cavity. Histology in TPM1-mutation hearts is indistinguishable from that of other sarcomeric causes, so the node is a faithful specialization of the generic ventricular-remodeling node rather than a TPM1-specific pathology. Human cardiac biopsies carrying TPM1 variants show loss of sarcomeric structure.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology. Cardiac Fibroblast CL:0002548 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiac Fibroblast, annotated with fibroblast of cardiac tissue (CL:0002548). CL:0002548 is a cell type from the Cell Ontology.
Cardiac muscle hypertrophy in response to stress GO:0014898 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Cardiac muscle hypertrophy in response to stress (GO:0014898). GO:0014898 is a biological process from the Gene Ontology. ↑ INCREASED Sarcomere organization GO:0045214 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Sarcomere organization (GO:0045214). GO:0045214 is a biological process from the Gene Ontology. ⚠ ABNORMAL
interventricular septum UBERON:0002094 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in interventricular septum (UBERON:0002094). UBERON:0002094 is an anatomical location from the Uberon multi-species anatomy ontology. left ventricle UBERON:0002084 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in left ventricle, annotated with heart left ventricle (UBERON:0002084). UBERON:0002084 is an anatomical location from the Uberon multi-species anatomy ontology.
Experimental models
Alpha-TM180 transgenic mouse (TPM1 Glu180Gly) OTHER
Downstream
Diastolic Dysfunction and Left Ventricular Outflow Tract Obstruction
Arrhythmogenic Substrate and Sudden Cardiac Death
Show evidence (4 references)
PMID:9060904 SUPPORT Human Clinical
"The Asp175Asn mutation caused cardiac histopathologic findings of myocyte hypertrophy, disarray and replacement fibrosis."
Human histopathology in TPM1-mutation carriers establishing all three components of this node.
PMID:9060904 SUPPORT Human Clinical
"On cardiac histopathologic study, defects in this sarcomere thin filament component are indistinguishable from other genetic etiologies of hypertrophic cardiomyopathy."
Justifies modeling this node as a conformer of the generic cardiomyopathy remodeling module rather than as a TPM1-specific tissue lesion.
PMID:32882290 SUPPORT Human Clinical
"Human cardiac biopsies with TPM1 variants revealed loss of sarcomeric structures."
Confirms structural sarcomeric disorganization in human myocardium carrying TPM1 variants.
+ 1 more reference
Diastolic Dysfunction and Left Ventricular Outflow Tract Obstruction
The stiffened, hypertrophied, fibrotic ventricle fills poorly, and when hypertrophy is asymmetric and septal it can also obstruct the left ventricular outflow tract dynamically. The clinical result is exertional dyspnoea, chest pain, and reduced exercise capacity with preserved or supranormal ejection fraction. Thin-filament HCM as a class tends to produce relatively less hypertrophy and less outflow obstruction than thick-filament HCM while carrying more heart-failure morbidity, so the obstructive presentation should not be assumed in a TPM1 carrier.
Relaxation of cardiac muscle GO:0055119 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Relaxation of cardiac muscle (GO:0055119). GO:0055119 is a biological process from the Gene Ontology. ↓ DECREASED Heart contraction GO:0060047 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Heart contraction (GO:0060047). GO:0060047 is a biological process from the Gene Ontology. ⚠ ABNORMAL
left ventricle UBERON:0002084 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in left ventricle, annotated with heart left ventricle (UBERON:0002084). UBERON:0002084 is an anatomical location from the Uberon multi-species anatomy ontology.
Experimental models
Alpha-TM180 transgenic mouse (TPM1 Glu180Gly) OTHER
Downstream
Progressive Heart Failure
Show evidence (2 references)
PMID:32217077 SUPPORT Other
"Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy and is characterized by asymmetric left ventricular hypertrophy and diastolic dysfunction, and a frequent cause of sudden cardiac death at young age."
States the asymmetric-hypertrophy-plus-diastolic-dysfunction phenotype that this node represents. Evidence source is OTHER because this is a review.
PMID:36158814 SUPPORT Other
"A number of distinct clinical findings appear to be correlated with thin-filament mutations: greater degrees of restrictive cardiomyopathy and relatively less left ventricular (LV) hypertrophy and LV outflow tract obstruction than that seen with thick filament mutations, increased morbidity..."
The key CMH3-specific qualifier on this node: thin-filament HCM skews away from obstruction and toward restrictive physiology, heart failure, and arrhythmia.
Arrhythmogenic Substrate and Sudden Cardiac Death
Myofibre disarray, interstitial and replacement fibrosis, and abnormal calcium handling together create a substrate for reentrant and triggered ventricular arrhythmia. Sudden cardiac death is the outcome that dominates risk stratification in CMH3, and several TPM1 pedigrees have been ascertained through a sudden death. Risk is markedly allele-dependent: sudden-death risk was low in most p.Arg21Leu carriers, whereas other alleles - and digenic thin-plus-thick-filament genotypes - have been associated with severe disease and sudden death.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Regulation of heart rate by cardiac conduction GO:0086091 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Regulation of heart rate by cardiac conduction (GO:0086091). GO:0086091 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Show evidence (5 references)
PMID:36613463 SUPPORT Human Clinical
"Hypertrophic cardiomyopathy (HCM), caused by mutations in thin filament proteins, manifests as moderate cardiac hypertrophy and is associated with sudden cardiac death (SCD)."
States the thin-filament HCM phenotype of moderate hypertrophy with sudden death risk, in a report of a de novo TPM1 variant identified in a sudden death victim.
PMID:38874371 SUPPORT Human Clinical
"The identification of a novel TPM1 variant in a family with HCM and SCD underscores the critical role of genetic screening in at-risk families."
Documents a TPM1 HCM pedigree ascertained through sudden cardiac death.
PMID:33642254 SUPPORT Human Clinical
"Calculated HCM sudden death risk was low in 34 carriers (77.5%), intermediated in 8 (18%), and high in only 2 (4.5%)."
Shows that sudden-death risk in the largest single-variant TPM1 series was low for most carriers. PARTIAL because it establishes allele-dependent low risk rather than supporting the arrhythmogenic mechanism itself.
+ 2 more references
Progressive Heart Failure
A minority of CMH3 patients progress to symptomatic heart failure, and thin-filament HCM as a class carries higher heart-failure morbidity than thick-filament HCM. Outcome nonetheless remains strongly allele-dependent: survival free of cardiovascular death or transplant was 87.5% at 50 years in the p.Arg21Leu founder series, and near-normal life expectancy was reported for Asp175Asn.
Heart contraction GO:0060047 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Heart contraction (GO:0060047). GO:0060047 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Show evidence (2 references)
PMID:33642254 SUPPORT Human Clinical
"Survival free of cardiovascular death or heart transplant was 87.5% at 50 years."
Quantifies transplant-free survival, the clinical endpoint of this node, for the best-characterized TPM1 HCM allele.
PMID:9060904 SUPPORT Human Clinical
"In contrast, prognosis reflected genotype; near normal life expectancy is found in hypertrophic cardiomyopathy caused by the alpha-tropomyosin mutation Asp175Asn."
Establishes that prognosis in CMH3 is genotype-dependent and can be favourable, tempering the generic heart-failure endpoint.
Divergent Non-Hypertrophic Remodeling Phenotypes
Not every TPM1 variant produces hypertrophy. The same gene causes dilated, restrictive, and left ventricular noncompaction cardiomyopathy, and compound-heterozygous TPM1 genotypes have produced restrictive disease in a child whose singly heterozygous relatives had diastolic dysfunction and HCM. Paired mechanistic study of E62Q (hypertrophic) and E54K (dilated) attributes the divergence to which physical property of tropomyosin the substitution perturbs. This node is included because it constrains how a TPM1 finding may be interpreted clinically, not because it is part of the CMH3 causal chain.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Show evidence (4 references)
PMID:39436707 SUPPORT Computational
"In E62Q, increased calcium sensitivity and hypercontractility was explained most accurately by a reduction in effective molecular stiffness of tropomyosin and alterations in its interactions with the actin thin filament that favor the "closed" regulatory state."
Gives the proposed molecular basis of the hypertrophic branch, against which the dilated branch is contrasted in the same study.
PMID:39436707 SUPPORT Computational
"By contrast, the E54K mutation appeared to act via long-range allosteric interactions to increase the association rate of the C-terminal troponin I mobile domain to tropomyosin/actin."
The contrasting dilated-phenotype mechanism, establishing that the divergence has a molecular explanation rather than being purely stochastic.
PMID:32882290 SUPPORT Human Clinical
"We identified a large family with DCM carrying a recently identified TPM1 gene variant (T201M) and a child with RCM with compound heterozygote TPM1 variants (E62Q and M281T) whose family members carrying single variants show diastolic dysfunction and HCM."
Shows the hypertrophic, restrictive, and dilated expressions of TPM1 variation coexisting within families, including allele-dose dependence.
+ 1 more reference
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Hypertrophic Cardiomyopathy 3 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

14
Cardiovascular 7
Hypertrophic Cardiomyopathy OBLIGATE HP:0001639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertrophic cardiomyopathy (HP:0001639). HP:0001639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:8205619 SUPPORT Human Clinical
"We demonstrate that missense mutations (Asp175Asn; Glu180Gly) in the alpha-tropomyosin gene cause familial hypertrophic cardiomyopathy (FHC) linked to chromosome 15q2."
Establishes hypertrophic cardiomyopathy as the phenotype caused by TPM1 variants. The frequency is OBLIGATE because it is the defining feature of the disease entity, not an associated finding.
Left Ventricular Hypertrophy VERY_FREQUENT HP:0001712 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Left ventricular hypertrophy (HP:0001712). HP:0001712 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:9060904 SUPPORT Human Clinical
"The severity and distribution of left ventricular hypertrophy varied considerably in affected members from the three families"
Documents left ventricular hypertrophy in all three TPM1 Asp175Asn kindreds and its variable severity and distribution. Frequency VERY_FREQUENT because hypertrophy was present across affected members of every reported kindred while penetrance is incomplete.
PMID:38874371 SUPPORT Human Clinical
"Hypertrophic cardiomyopathy (HCM) is an autosomal dominant genetic cardiac disorder characterized by unexplained left ventricular hypertrophy."
Confirms unexplained left ventricular hypertrophy as the cardinal finding, in a TPM1-variant pedigree report.
Left Ventricular Diastolic Dysfunction HP:0025168 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Left ventricular diastolic dysfunction (HP:0025168). HP:0025168 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:34319370 SUPPORT In Vitro
"These tissues showed disease features similar to those of the patients, including cellular hypertrophy, hypercontractility, and diastolic dysfunction."
Diastolic dysfunction reproduced in patient-derived engineered heart tissue and explicitly matched to the donors' clinical phenotype.
PMID:32882290 SUPPORT Human Clinical
"whose family members carrying single variants show diastolic dysfunction and HCM"
Documents diastolic dysfunction in heterozygous TPM1 variant carriers in a clinical family study.
Sudden Cardiac Death HP:0001645 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sudden cardiac death (HP:0001645). HP:0001645 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:38874371 SUPPORT Human Clinical
"In this study, we aimed to characterize the clinical and molecular phenotype of HCM in an Iranian pedigree with SCD."
A TPM1 HCM pedigree ascertained through sudden cardiac death.
PMID:38223010 SUPPORT Human Clinical
"However, some high-risk mutations causing sudden cardiac death are also known in this gene."
States that high-risk sudden-death alleles exist within TPM1, the basis for allele-specific risk stratification.
PMID:12651045 SUPPORT Human Clinical
"The clinical data suggest a malignant phenotype at young age with a variable clinical manifestation and penetrance at older age."
Documents a malignant young-onset TPM1 sudden-death phenotype coexisting with mild disease in older relatives of the same family.
Congestive Heart Failure OCCASIONAL HP:0001635 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congestive heart failure (HP:0001635). HP:0001635 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38874371 SUPPORT Human Clinical
"It can cause a wide spectrum of clinical manifestations, ranging from asymptomatic to heart failure and sudden cardiac death (SCD)."
Places heart failure on the CMH3 clinical spectrum. The OCCASIONAL band reflects that most carriers in the largest series remained free of cardiovascular death or transplant at 50 years.
PMID:36158814 SUPPORT Other
"increased morbidity associated with heart failure, increased arrhythmia burden and potentially higher mortality"
Supports elevated heart-failure morbidity as a thin-filament class feature. PARTIAL because the claim is class-level rather than TPM1-specific.
Non-Sustained Ventricular Tachycardia HP:0004756 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Non-sustained ventricular tachycardia, annotated with Ventricular tachycardia (HP:0004756). HP:0004756 is a phenotype from the Human Phenotype Ontology.
Frequency deliberately omitted. Cohort percentages for NSVT in thin-filament HCM circulate in the literature but are not present in any abstract cached for this entry, and the direction of the effect is disputed between cohorts. HPO has no non-sustained-VT term, so the general term carries a narrower preferred_term.
Show evidence (1 reference)
PMID:36158814 SUPPORT Other
"high risk of SCD with positive family history, non-sustained ventricular arrythmias and abnormal"
Places non-sustained ventricular arrhythmia among the risk markers in thin-filament HCM. The snippet is a mid-sentence span because the cached PDF renders "affected by thin filament" with typographic ligatures that break exact substring matching. PARTIAL because this is a narrative review of the thin-filament class rather than a TPM1-specific measurement, and because the same class's prospective cohort data conflict with it.
Syncope HP:0001279 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Syncope (HP:0001279). HP:0001279 is a phenotype from the Human Phenotype Ontology.
Frequency deliberately omitted - no cached source reports a syncope rate in TPM1 or thin-filament HCM.
Show evidence (1 reference)
PMID:36158814 SUPPORT Other
"a history of syncope due to arrhythmia, LV apical aneurysm or LV systolic dysfunction"
Places arrhythmic syncope among the ICD indications. PARTIAL because it is a general HCM recommendation restated in a thin-filament review, not a TPM1-specific observation.
Constitutional 1
Exercise Intolerance HP:0003546 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Exercise intolerance (HP:0003546). HP:0003546 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32871100 SUPPORT Human Clinical
"Treatment with mavacamten improved exercise capacity, LVOT obstruction, NYHA functional class, and health status in patients with obstructive hypertrophic cardiomyopathy."
Establishes reduced exercise capacity as a treatable clinical feature of obstructive HCM. PARTIAL because the trial enrolled obstructive HCM generally rather than genotyped TPM1 carriers.
Other 6
Asymmetric Septal Hypertrophy HP:0001670 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Asymmetric septal hypertrophy (HP:0001670). HP:0001670 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32217077 SUPPORT Other
"Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy and is characterized by asymmetric left ventricular hypertrophy and diastolic dysfunction, and a frequent cause of sudden cardiac death at young age."
Supports asymmetric hypertrophy as characteristic of HCM. PARTIAL because the statement is HCM-wide rather than TPM1-specific; the TPM1 Asp175Asn kindreds showed anterior, posterior, and free-wall predominant patterns.
Myocardial Sarcomeric Disarray HP:0031333 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myocardial sarcomeric disarray (HP:0031333). HP:0031333 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9060904 SUPPORT Human Clinical
"The Asp175Asn mutation caused cardiac histopathologic findings of myocyte hypertrophy, disarray and replacement fibrosis."
Direct histopathological documentation of myocyte disarray in hearts carrying a TPM1 HCM variant.
Myocardial Fibrosis HP:0001685 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myocardial fibrosis (HP:0001685). HP:0001685 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9060904 SUPPORT Human Clinical
"The Asp175Asn mutation caused cardiac histopathologic findings of myocyte hypertrophy, disarray and replacement fibrosis."
Documents replacement fibrosis on histopathology in TPM1 Asp175Asn carriers.
Left Ventricular Outflow Tract Obstruction OCCASIONAL HP:0032092 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Left ventricular outflow tract obstruction (HP:0032092). HP:0032092 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36158814 SUPPORT Other
"greater degrees of restrictive cardiomyopathy and relatively less left ventricular (LV) hypertrophy and LV outflow tract obstruction than that seen with thick filament mutations"
Establishes that outflow obstruction occurs but is less frequent in thin-filament HCM. The OCCASIONAL band is a qualitative mapping of "less than thick-filament HCM" (where obstruction affects roughly 60% of patients) and is marked PARTIAL because no TPM1-specific rate is reported.
Restrictive Cardiomyopathy VERY_RARE HP:0001723 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Restrictive cardiomyopathy (HP:0001723). HP:0001723 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32882290 SUPPORT Human Clinical
"a child with RCM with compound heterozygote TPM1 variants (E62Q and M281T)"
Documents restrictive cardiomyopathy in a TPM1 compound heterozygote whose singly heterozygous relatives had HCM, i.e. an allele-dose-dependent restrictive expression within a CMH3 family.
Abnormal Electrocardiogram Abnormal EKG HP:0003115 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal EKG (HP:0003115). HP:0003115 is a phenotype from the Human Phenotype Ontology.
The cohort is sarcomere-variant carriers across genes, of whom TPM1 carriers were 3.2% (9 individuals), so this is class-level rather than TPM1-specific evidence. It is curated at SUPPORT rather than PARTIAL because the claim being made - that ECG change precedes diagnosis in sarcomeric HCM - is exactly what the cohort measured.
Show evidence (1 reference)
PMID:32731933 SUPPORT Human Clinical
"Of these, 45 (54.2%) of 83 had an abnormal ECG before fulfilling the diagnostic criteria and this was first documented a median 4.4 years"
Establishes ECG abnormality as an antecedent of overt HCM rather than a concomitant of it, which is the empirical justification for the serial ECG surveillance this entry curates as cascade testing.
🧬

Genetic Associations

2
TPM1
Gene: TPM1 hgnc:12010 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TPM1 (hgnc:12010). hgnc:12010 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (6 references)
PMID:32731933 SUPPORT Human Clinical
"At 15 years follow-up, estimated HCM penetrance by causal gene was as follows: MYBPC3 43% (95% CI: 32% to 57%), MYH7 66% (95% CI: 47% to 83%), TNNI3 17% (95% CI: 7% to 39%), TNNT2 50% (95% CI: 30% to 74%), TPM1 42% (95% CI: 11% to 92%)"
The only gene-specific penetrance estimate available for TPM1: 42% at 15 years. It is quoted with its full confidence interval and alongside the other genes deliberately, because the interval - 11% to 92% - overlaps every other gene in the table and the estimate rests on 9 carriers across 3 families. PARTIAL for that reason: the point estimate is not distinguishable from the other sarcomere genes and must not be counselled as though it were a TPM1-specific figure. Quoting the bare 42% without the interval would be worse than omitting it.
PMID:32731933 SUPPORT Human Clinical
"Overall, HCM penetrance at 15 years follow-up was 46%"
The all-gene benchmark the TPM1 estimate should be read against; the reported interval for this figure is 38% to 54%, quoted here in the explanation rather than the snippet because the validator normalises square-bracketed text. TPM1's 42% sits inside that interval, which is the clearest way to see that the gene-specific figure carries no information beyond the cohort average.
CGGV:assertion_32e7ed58-ee49-4719-b48e-7fad58012319-2023-12-18T170000.000Z SUPPORT Other
"TPM1 | HGNC:12010 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Definitive"
ClinGen classifies the TPM1-hypertrophic cardiomyopathy gene-disease relationship as Definitive.
+ 3 more references
MYH7 (digenic modifier)
Gene: MYH7 hgnc:7577 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MYH7 (hgnc:7577). hgnc:7577 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: COOPERATING
Show evidence (3 references)
PMID:25607779 SUPPORT Human Clinical
"Thus, we strongly suggest that the coexistence of these digenic mutations is rare, but leads to severe hypertrophy in a South Indian familial hypertrophic cardiomyopathy (FHCM)."
Reports the digenic TPM1-plus-MYH7 genotype and its association with more severe hypertrophy.
PMID:25607779 SUPPORT Human Clinical
"Patient #1 showed a more severe disease phenotype, with poor prognosis and a family history of sudden cardiac death, than patient #2."
Within-study contrast between the digenic and the single-TPM1-variant proband, supporting the modifier claim.
PMID:33642254 SUPPORT Human Clinical
"Six percent of carriers were homozygous and 18% had an additional variant."
Quantifies how often a TPM1 HCM carrier also carries a second variant, the population-level basis for treating multi-variant genotype as a modifier.
💊

Medical Actions

3
Cardiac Myosin Inhibition (Mavacamten)
Category: Therapeutic Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: mavacamten Relation: this treatment uses this therapeutic agent This treatment uses mavacamten.
Mavacamten is a first-in-class allosteric cardiac myosin inhibitor that reduces the number of force-generating crossbridges. It is mechanistically well matched to CMH3, whose lesion is failure to keep crossbridges inhibited: in patient-derived engineered heart tissue carrying TPM1 E192K, chronic mavacamten abolished the contractile difference from control and reversed cardiomyocyte hypertrophy. In symptomatic obstructive HCM generally, the phase 3 EXPLORER-HCM trial showed improvement in exercise capacity, outflow gradient, NYHA class, and health status. The gene-specific evidence is preclinical; the clinical trial evidence is genotype-agnostic.
Mechanism Target:
INHIBITS Cardiomyocyte Hypercontractility and Impaired Relaxation — Myosin inhibition reduces the number of force-generating crossbridges, directly opposing the hypercontractile node that the TPM1 regulatory defect produces.
Target Phenotypes: Left ventricular outflow tract obstruction HP:0032092 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Left ventricular outflow tract obstruction (HP:0032092). HP:0032092 is a phenotype from the Human Phenotype Ontology. Exercise intolerance HP:0003546 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Exercise intolerance (HP:0003546). HP:0003546 is a phenotype from the Human Phenotype Ontology.
Show evidence (4 references)
PMID:34319370 SUPPORT In Vitro
"Chronic mavacamten treatment abolished contractile differences between control and TPM1 E192K engineered heart tissues and reversed hypertrophy in cardiomyocytes."
The gene-specific rationale: myosin inhibition corrects the contractile and hypertrophic phenotype of a TPM1 HCM variant in patient-derived tissue.
PMID:34319370 SUPPORT In Vitro
"These studies also provide direct evidence that myosin inhibition by mavacamten can counteract the hypertrophic effects of mutant tropomyosin."
Explicitly generalizes the result to mutant tropomyosin, i.e. to CMH3 as a class rather than to one allele.
PMID:32871100 SUPPORT Human Clinical
"Treatment with mavacamten improved exercise capacity, LVOT obstruction, NYHA functional class, and health status in patients with obstructive hypertrophic cardiomyopathy."
Pivotal clinical efficacy evidence. PARTIAL for CMH3 because EXPLORER-HCM enrolled symptomatic obstructive HCM without genotype stratification, and thin-filament HCM is less often obstructive.
+ 1 more reference
Implantable Cardioverter-Defibrillator for Sudden Death Prevention
Category: Therapeutic Action: implantable cardioverter-defibrillator placementNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is implantable cardioverter-defibrillator placement (NCIT:C80435). NCIT:C80435 is a clinical intervention from the NCI Thesaurus. Ontology label: Implantable Cardioverter-Defibrillator Placement NCIT:C80435
Risk-stratified ICD implantation is the intervention that addresses the dominant mortality risk in CMH3. Allele-specific data matter here: calculated sudden-death risk was low in 77.5% of p.Arg21Leu carriers, so a TPM1 diagnosis alone does not justify device therapy, whereas other TPM1 alleles have been reported in families ascertained through sudden death.
Target Phenotypes: Sudden cardiac death HP:0001645 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Sudden cardiac death (HP:0001645). HP:0001645 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33642254 SUPPORT Human Clinical
"Calculated HCM sudden death risk was low in 34 carriers (77.5%), intermediated in 8 (18%), and high in only 2 (4.5%)."
Provides the allele-specific risk distribution that drives the device-versus-surveillance decision in the best-characterized CMH3 allele.
PMID:38874371 SUPPORT Human Clinical
"Early detection of pathogenic variants can facilitate timely intervention and management, potentially reducing the risk of SCD in individuals with HCM."
Supports intervention to reduce sudden-death risk after molecular diagnosis. PARTIAL because the paper does not itself evaluate device therapy.
Genetic Counseling and Family Screening
Category: Counseling / Informational Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Genetic counseling covers the autosomal dominant 50% recurrence risk, age-dependent and sex-modified incomplete penetrance, the possibility of a second sarcomere variant in the family, and the implications for reproductive and life planning. It is paired with cascade genetic testing and longitudinal cardiac surveillance of carriers.
Show evidence (2 references)
PMID:38874371 SUPPORT Human Clinical
"The identification of a novel TPM1 variant in a family with HCM and SCD underscores the critical role of genetic screening in at-risk families."
Directly supports family genetic screening after a TPM1 CMH3 diagnosis.
PMID:33642254 SUPPORT Human Clinical
"At the age of 70 years, 17% of males and 46% of female carriers were unaffected."
Supplies the penetrance figures that counseling must convey, including the substantial chance of lifelong non-penetrance in female carriers.
🔬

Diagnosis

4
Echocardiographic Demonstration of Unexplained Left Ventricular Hypertrophy
CMH3 is diagnosed, like all HCM, by imaging demonstration of increased left ventricular wall thickness that is not explained by abnormal loading conditions. Echocardiography defines the distribution of hypertrophy, the presence and gradient of dynamic outflow obstruction, and diastolic function; hypertrophic pattern differs by causal gene, so echocardiographic morphology can inform which gene to prioritise.
Show evidence (2 references)
PMID:38223010 SUPPORT Human Clinical
"Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disorder characterised by unexplained left ventricular hypertrophy in the absence of abnormal loading conditions."
States the diagnostic criterion applied in a TPM1-variant family report.
PMID:37561025 SUPPORT Human Clinical
"Our findings underscore a strong link between hypertrophic patterns and genetic variants in HCM, providing a foundation for more accurate genetic testing and personalized management of HCM patients."
Supports using echocardiographic hypertrophy pattern to guide genetic testing. PARTIAL because the reported gene-pattern associations concern MYBPC3, MYH7, ALPK3, TTN and OBSCN rather than TPM1 specifically.
Sarcomere Gene Panel or Exome Sequencing
Molecular confirmation requires sequencing of the sarcomere genes; TPM1 is a standard panel component. Because TPM1 accounts for only a small share of cases, the diagnosis is usually made as part of a multi-gene panel or exome, with segregation analysis in relatives to establish causality. Multi-variant genotypes are common enough that a TPM1 finding should not stop the search.
Show evidence (3 references)
PMID:38874371 SUPPORT Human Clinical
"Whole-exome sequencing (WES) was performed in all available family members to identify the causal variant, which was validated, and segregation analysis was conducted via Sanger sequencing."
Describes the exome-plus-segregation workflow by which a novel TPM1 CMH3 allele was established.
PMID:33642254 SUPPORT Human Clinical
"TPM1 was evaluated by next-generation sequencing in 10 561 unrelated probands with inherited heart diseases."
Documents next-generation sequencing of TPM1 as routine practice in inherited-heart-disease diagnostics.
PMID:39132495 SUPPORT Other
"We report 29 genes with definitive, strong or moderate evidence of causation for HCM or isolated LVH, including sarcomere, sarcomere-associated and syndromic conditions."
Defines the evidence-backed gene set that an HCM panel should cover, of which TPM1 is one. PARTIAL because the quoted conclusion is panel-wide; the TPM1-specific Definitive classification is carried by the ClinGen CGGV assertion row cited elsewhere in this entry.
Cascade Genetic Testing of At-Risk Relatives
Once a pathogenic TPM1 variant is identified in a proband, predictive testing of first-degree relatives identifies carriers who need longitudinal cardiac surveillance and releases non-carriers from it. Because penetrance is incomplete and age-dependent - only half of male and a quarter of female p.Arg21Leu carriers are diagnosed by age 50 - a normal echocardiogram in a young carrier does not exclude later disease.
Show evidence (4 references)
PMID:38874371 SUPPORT Human Clinical
"Early detection of pathogenic variants can facilitate timely intervention and management, potentially reducing the risk of SCD in individuals with HCM."
States the rationale for cascade testing in a TPM1 HCM family with sudden cardiac death.
PMID:33642254 SUPPORT Human Clinical
"At the age of 70 years, 17% of males and 46% of female carriers were unaffected."
Quantifies lifelong non-penetrance, the reason cascade-identified carriers need continuing rather than one-off surveillance.
PMID:32731933 SUPPORT Human Clinical
"Following a first negative screening, approximately 50% of SP mutation carriers develop HCM over 15 years of follow-up."
Quantifies conversion after an initially negative screen, the central argument for repeat rather than one-off surveillance. PARTIAL because the cohort pooled sarcomere-protein genes, of which TPM1 carriers were a small minority.
+ 1 more reference
Cardiac Magnetic Resonance with Late Gadolinium Enhancement
CMR does two things in this genotype that echocardiography does not. It measures wall thickness more reliably in the segments where thin-filament disease is mildest - the one prospective thin-filament cohort found the difference from thick-filament disease significant by both echo and CMR, with the CMR comparison the stronger of the two - and late gadolinium enhancement quantifies the fibrotic substrate that this entry curates as a phenotype and as an arrhythmic mechanism. The second matters disproportionately here because the hypertrophy in thin-filament disease is milder than in thick-filament disease, so wall thickness alone understates disease burden in exactly this population.
Cardiac magnetic resonance imaging NCIT:C16809 NCI Thesaurus (NCIT)
Results: Maximum wall thickness, typically lower than in thick-filament HCM, and late gadolinium enhancement marking replacement fibrosis.
The late-gadolinium-enhancement prevalence figure that circulates for thin-filament HCM is not quotable from any abstract cached for this entry - it comes from the full text of the cohort study. The role of LGE is stated here on the strength of the fibrosis phenotype this entry already curates rather than on an unverified percentage.
Show evidence (1 reference)
DOI:10.3390/jcm14030866 SUPPORT Human Clinical
"individuals with thin-filament mutations exhibited significantly lower maximum left ventricular wall thickness, as measured by both echocardiography (p = 0.024) and cardiac magnetic resonance (p = 0.006)"
Establishes CMR as a measuring modality in this population and the thinner-phenotype finding that makes imaging interpretation genotype-dependent.
📈

Progression

3
Preclinical genotype-positive phenotype-negative
Show evidence (1 reference)
PMID:33642254 SUPPORT Human Clinical
"TPM1 p.Arg21Leu is a pathogenic HCM variant associated with late-onset/incomplete penetrance and a generally favorable prognosis."
Establishes a long genotype-positive, phenotype-negative phase for the best-characterized CMH3 allele.
Age: Adulthood
Show evidence (1 reference)
PMID:33642254 SUPPORT Human Clinical
"The cumulative probability of diagnosis in carriers was 50% at the age of 50 years for males, and was 25% in female carriers."
Gives the age distribution of clinical onset in TPM1 carriers, with a sex effect.
Paediatric onset
Show evidence (1 reference)
PMID:32744700 SUPPORT Human Clinical
"to our knowledge, this is the first report of the homozygous missense variation p.Gly3Arg in TPM1 associated with familial autosomal recessive pediatric HCM and PDA."
Documents that biallelic TPM1 genotypes can present in childhood, in contrast to the late-onset heterozygous course.
📊

Prevalence

1
Familial hypertrophic cardiomyopathy referral cohorts
Unknown Not yet documented
No population-based prevalence estimate exists for the TPM1-specific form of hypertrophic cardiomyopathy. What is documented is the share of HCM cases attributable to TPM1, which is small: roughly 3% of familial cases in the original referral-centre survey and under 1% in more recent series. The population occurrence of hypertrophic cardiomyopathy as a whole (about 1 in 500) is curated on the umbrella Hypertrophic Cardiomyopathy entry and is not duplicated here.
Show evidence (1 reference)
PMID:7898523 SUPPORT Human Clinical
"Mutations in alpha-tropomyosin are a rare cause of familial hypertrophic cardiomyopathy, accounting for approximately 3 percent of cases."
Quantifies the TPM1 share of familial HCM cases in the founding referral-centre cohort. PARTIAL because a case fraction within an ascertained HCM series is not a population prevalence.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Hypertrophic Cardiomyopathy 3:

Thick-Filament Sarcomeric HCM (MYH7, MYBPC3)
Overlapping Features The other, far commoner sarcomeric causes of hypertrophic cardiomyopathy. Clinically and histologically overlapping with CMH3 - the histopathology is explicitly indistinguishable - so the distinction is molecular. Thick-filament disease tends to produce more hypertrophy and more outflow obstruction and less restrictive physiology than thin-filament disease.
Distinguishing Features
  • Distinguished by the causal gene on sequencing, not by histology
  • Greater degrees of LV hypertrophy and outflow obstruction than thin-filament HCM
  • Distinct hypertrophy distributions on echocardiography (mid-septal for MYBPC3, higher septum-to-posterior-wall ratio for MYH7)
Show evidence (3 references)
PMID:9060904 SUPPORT Human Clinical
"On cardiac histopathologic study, defects in this sarcomere thin filament component are indistinguishable from other genetic etiologies of hypertrophic cardiomyopathy."
Establishes that histology cannot separate CMH3 from other sarcomeric HCM.
PMID:36158814 SUPPORT Other
"greater degrees of restrictive cardiomyopathy and relatively less left ventricular (LV) hypertrophy and LV outflow tract obstruction than that seen with thick filament mutations"
Gives the phenotypic tendencies that differentiate thin-filament from thick-filament HCM at the group level.
PMID:37561025 SUPPORT Human Clinical
"Mid-septal hypertrophy was found to be associated predominantly with myosin binding protein C3 (MYBPC3) variants, while a higher septum-to-posterior wall ratio correlated with myosin heavy chain 7 (MYH7) variants."
Provides the imaging correlates of the two main thick-filament genes.
🧫

Experimental Models

4
Alpha-TM180 transgenic mouse (TPM1 Glu180Gly) OTHER
Cardiac-restricted transgenic mouse expressing alpha-tropomyosin carrying the founding CMH3 allele Glu180Gly. The flagship in vivo model of thin-filament HCM and the only model in this entry that reproduces the whole-organ, whole-organism course: early concentric hypertrophy with fibrosis and atrial enlargement, diastolic dysfunction, increased myofilament calcium sensitivity, and death between four and five months.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Organism
mouse NCBITaxon:10090 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in mouse, annotated with Mus musculus (NCBITaxon:10090). NCBITaxon:10090 is an organism from the NCBI Taxonomy.
Publication
PMID:11603924
Pathograph links
Alpha-Tropomyosin Thin Filament Regulatory Defect
Cardiomyocyte Hypertrophy with Myofiber Disarray and Interstitial Fibrosis
Diastolic Dysfunction and Left Ventricular Outflow Tract Obstruction
Findings
Ventricular concentric hypertrophy, fibrosis, and atrial enlargement within one month; progressive worsening with death between four and five months; diastolic dysfunction and increased myofilament calcium sensitivity.
Model type is recorded as OTHER because the ExperimentalModelType enum has no transgenic-animal value; the organism binding carries the actual model identity. This is a transgenic overexpression model, not an endogenous-locus knock-in, so it does not reproduce the human 1:1 mutant-to-wild-type stoichiometry - see the HUMAN_MODEL_MISMATCH discussion.
Show evidence (2 references)
PMID:11603924 SUPPORT Model Organism
"This study developed transgenic mouse lines that encode an FHC mutation in alpha-tropomyosin"
Describes construction of the model.
PMID:11603924 SUPPORT Model Organism
"The disease-associated changes progressively increase and result in death between 4 and 5 months."
Gives the model's natural history and endpoint.
Patient-derived engineered heart tissue expressing TPM1 E192K IPSC_DERIVED_MODEL
Three-dimensional engineered heart tissue generated from cardiomyocytes derived from patients carrying TPM1 E192K. Reproduces cellular hypertrophy, hypercontractility, and diastolic dysfunction, and was used to demonstrate rescue by chronic mavacamten.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Publication
PMID:34319370
Pathograph links
Cardiomyocyte Hypercontractility and Impaired Relaxation
Findings
Cellular hypertrophy, hypercontractility, and diastolic dysfunction matching the donors' clinical features; contractile differences and hypertrophy were abolished by chronic mavacamten.
Show evidence (1 reference)
PMID:34319370 SUPPORT In Vitro
"To assess the physiological impact of the mutation, we generated patient-derived engineered heart tissues expressing E192K."
Describes construction of the model.
Genetically engineered heart tissue expressing TPM1 S215L IPSC_DERIVED_MODEL
Three-dimensional genetically engineered heart tissue expressing the TPM1 S215L variant, used together with molecular-dynamics simulation and a Markov model of thin-filament activation to reclassify a variant of unknown significance as pathogenic.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Publication
PMID:36896133
Pathograph links
Loss of Crossbridge Inhibition and Increased Myofilament Calcium Sensitivity
Cardiomyocyte Hypercontractility and Impaired Relaxation
Findings
Hypercontractility, upregulation of hypertrophic gene markers, and diastolic dysfunction, supporting reclassification of S215L as pathogenic.
Show evidence (1 reference)
PMID:36896133 SUPPORT In Vitro
"Three-dimensional genetically engineered heart tissues expressing TPM1 S215L exhibited hypercontractility, upregulation of hypertrophic gene markers, and diastolic dysfunction."
Describes the model and its phenotype.
Patient hiPSC-derived cardiomyocytes carrying TPM1 Asp175Asn IPSC_DERIVED_MODEL
Human induced pluripotent stem cell-derived cardiomyocytes from a carrier of the founding CMH3 allele Asp175Asn, compared side by side with MYBPC3-Gln1061X cardiomyocytes to test whether thin- and thick-filament HCM differ at the cellular level.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Publication
PMID:27057166
Pathograph links
Cardiomyocyte Hypercontractility and Impaired Relaxation
Findings
Pathological HCM phenotype with cellular enlargement, altered calcium handling and electrophysiology, and a gene-expression profile distinct from the thick-filament comparator.
Show evidence (1 reference)
PMID:27057166 SUPPORT In Vitro
"Both types of HCM-CMs displayed pathological phenotype of HCM but, more importantly, we found differences between CMs carrying either MYBPC3-Gln1061X or TPM1-Asp175Asn gene mutation in their cellular size, Ca(2+) handling, and electrophysiological properties, as well as their gene expression profiles."
Describes the model and the mutation-specific result.
{ }

Source YAML

click to show 
name: Hypertrophic Cardiomyopathy 3
creation_date: "2026-08-01T00:00:00Z"
synonyms:
- CMH3
- TPM1 hypertrophic cardiomyopathy
- hypertrophic cardiomyopathy caused by mutation in TPM1
- hypertrophic cardiomyopathy type 3
- cardiomyopathy, hypertrophic, 3
- cardiomyopathy, familial hypertrophic, 3
description: >-
  Hypertrophic cardiomyopathy 3 (CMH3) is the TPM1-related form of familial
  hypertrophic cardiomyopathy. TPM1 encodes alpha-tropomyosin, the elongated
  coiled-coil dimer that lies in the groove of the actin thin filament and,
  together with the troponin complex, gates myosin access to actin across the
  blocked, closed, and open regulatory states of the cardiac sarcomere. CMH3 was
  one of the two founding observations that established hypertrophic
  cardiomyopathy as a disease of the sarcomere: missense variants at the
  chromosome 15q locus (Asp175Asn, Glu180Gly) were shown in 1994 to cosegregate
  with familial hypertrophic cardiomyopathy. Because tropomyosin's job is
  inhibitory, the recurring molecular consequence of HCM-associated TPM1 variants
  is a failure to keep crossbridges switched off: molecular-dynamics,
  in vitro motility, and engineered-heart-tissue studies of S215L, E192K, D219V,
  and E62Q converge on destabilization of the inhibited regulatory state, higher
  myofilament calcium sensitivity or residual actomyosin activity at low calcium,
  hypercontractility, and impaired relaxation, with induction of a hypertrophic
  gene program downstream. The clinical picture is that of hypertrophic
  cardiomyopathy generally - unexplained left ventricular hypertrophy, myocyte
  hypertrophy with disarray and replacement fibrosis on histology, diastolic
  dysfunction, arrhythmia, and a risk of sudden cardiac death - but TPM1 is a
  minority cause, historically about 3% of familial cases, and outcome is
  strongly variant-dependent: the founder variant p.Arg21Leu shows late-onset,
  incomplete penetrance and generally favourable prognosis, while other alleles
  have been reported in families ascertained through sudden cardiac death. TPM1
  is also an allelic cause of dilated, restrictive, and noncompaction
  cardiomyopathy, and disentangling which molecular consequence steers a carrier
  toward the hypertrophic rather than the dilated phenotype is an active research
  question.
category: Genetic
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
disease_term:
  preferred_term: hypertrophic cardiomyopathy 3
  term:
    id: MONDO:0007267
    label: hypertrophic cardiomyopathy 3
parents:
- Hypertrophic Cardiomyopathy
- Genetic Disorder
prevalence:
- population: Familial hypertrophic cardiomyopathy referral cohorts
  measure_type: UNKNOWN
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    No population-based prevalence estimate exists for the TPM1-specific form of
    hypertrophic cardiomyopathy. What is documented is the share of HCM cases
    attributable to TPM1, which is small: roughly 3% of familial cases in the
    original referral-centre survey and under 1% in more recent series. The
    population occurrence of hypertrophic cardiomyopathy as a whole (about 1 in
    500) is curated on the umbrella Hypertrophic Cardiomyopathy entry and is not
    duplicated here.
  evidence:
  - reference: PMID:7898523
    reference_title: Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in alpha-tropomyosin are a rare cause of familial hypertrophic
      cardiomyopathy, accounting for approximately 3 percent of cases.
    explanation: >-
      Quantifies the TPM1 share of familial HCM cases in the founding
      referral-centre cohort. PARTIAL because a case fraction within an
      ascertained HCM series is not a population prevalence.
inheritance:
- name: Autosomal Dominant
  description: >-
    CMH3 is transmitted as an autosomal dominant trait, and the TPM1-HCM
    gene-disease relationship has been classified by ClinGen's Hereditary
    Cardiovascular Disease Gene Curation Expert Panel as Definitive with
    autosomal dominant inheritance. Penetrance is incomplete and age-dependent,
    and both severity and age at diagnosis are variant- and sex-dependent.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  evidence:
  - reference: CGGV:assertion_32e7ed58-ee49-4719-b48e-7fad58012319-2023-12-18T170000.000Z
    reference_title: "TPM1 / hypertrophic cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      TPM1 | HGNC:12010 | hypertrophic cardiomyopathy | MONDO:0005045 | AD |
      Definitive
    explanation: >-
      ClinGen's Hereditary Cardiovascular Disease GCEP records autosomal dominant
      inheritance for the TPM1-hypertrophic cardiomyopathy relationship with
      Definitive clinical validity.
  - reference: PMID:25607779
    reference_title: "Coexistence of Digenic Mutations in Both Thin (TPM1) and Thick (MYH7) Filaments of Sarcomeric Genes Leads to Severe Hypertrophic Cardiomyopathy in a South Indian FHCM."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of these, one mutant, S215L, was identified in two unrelated HCM cases
    explanation: >-
      Documents identification of the S215L allele in unrelated HCM probands in a
      family study reporting autosomal dominant cosegregation.
  - reference: PMID:33642254
    reference_title: "Genotype-phenotype correlations in hypertrophic cardiomyopathy: a multicenter study in Portugal and Spain of the TPM1 p.Arg21Leu variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The cumulative probability of diagnosis in carriers was 50% at the age of
      50 years for males, and was 25% in female carriers.
    explanation: >-
      Quantifies age-dependent, sex-modified incomplete penetrance in the largest
      single-variant TPM1 HCM pedigree series.
- name: Autosomal Recessive (Rare Homozygous)
  description: >-
    Homozygous TPM1 genotypes are rare but reported, including a homozygous exon
    1 missense variant in a non-consanguineous family with paediatric HCM, and 6%
    of carriers in the p.Arg21Leu founder series were homozygous. Homozygosity is
    a dose effect on the same dominant allele rather than a mechanistically
    distinct recessive disease.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:32744700
    reference_title: A novel homozygous TPM1 mutation in familial pediatric hypertrophic cardiomyopathy and in silico screening of potential targeting drugs.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      to our knowledge, this is the first report of the homozygous missense
      variation p.Gly3Arg in TPM1 associated with familial autosomal recessive
      pediatric HCM and PDA.
    explanation: >-
      Reports a homozygous TPM1 genotype segregating with paediatric hypertrophic
      cardiomyopathy, establishing that biallelic TPM1 disease occurs.
  - reference: PMID:33642254
    reference_title: "Genotype-phenotype correlations in hypertrophic cardiomyopathy: a multicenter study in Portugal and Spain of the TPM1 p.Arg21Leu variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Six percent of carriers were homozygous and 18% had an additional variant.
    explanation: >-
      Documents that homozygosity for a TPM1 HCM allele occurs at appreciable
      frequency in a founder population, alongside frequent additional
      sarcomere-gene variants.
mechanistic_hypotheses:
- hypothesis_group_id: tpm1_loss_of_crossbridge_inhibition
  hypothesis_label: Loss of tropomyosin-mediated crossbridge inhibition
  status: CANONICAL
  description: >-
    The canonical model of CMH3 is that HCM-associated TPM1 variants degrade
    tropomyosin's inhibitory function on the thin filament. Molecular-dynamics
    simulations show mutant tropomyosin is more flexible and its blocked/closed
    positioning on actin is destabilized; in vitro motility assays show higher
    calcium sensitivity of filament sliding and failure to inhibit sliding at low
    calcium; engineered heart tissues built from the same variants are
    hypercontractile with impaired relaxation and induce hypertrophic gene
    markers. Under this model the proximate lesion is excess residual actomyosin
    interaction rather than a loss of force-generating capacity.
  evidence:
  - reference: PMID:36896133
    reference_title: Mechanisms of pathogenicity in the hypertrophic cardiomyopathy-associated TPM1 variant S215L.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These simulations and experiments support the classification of S215L as a
      pathogenic mutation and support the hypothesis that an inability to
      adequately inhibit actomyosin interactions is the mechanism whereby
      thin-filament mutations cause HCM.
    explanation: >-
      States the loss-of-inhibition hypothesis explicitly as the conclusion of a
      combined simulation, motility-assay, and engineered-heart-tissue study of a
      TPM1 HCM variant.
  - reference: PMID:34319370
    reference_title: Loss of crossbridge inhibition drives pathological cardiac hypertrophy in patients harboring the TPM1 E192K mutation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These results suggest that the TPM1 E192K mutation triggers cardiomyocyte
      hypertrophy by permitting excess residual crossbridge activity.
    explanation: >-
      Independent confirmation of the same mechanism in a second TPM1 variant,
      using patient-derived engineered heart tissue.
- hypothesis_group_id: tpm1_calcium_buffering_signaling
  hypothesis_label: Myofilament calcium buffering as the initiator of hypertrophic signaling
  status: ALTERNATIVE
  description: >-
    A complementary account places the primary lesion one step downstream of the
    regulatory defect: because mutant thin filaments bind calcium more avidly,
    myofilament calcium buffering rises, diastolic calcium increases, reuptake
    slows, and calcium-dependent signaling through CaMKII, calcineurin/NFAT, and
    ERK is chronically engaged - providing the transcriptional drive for
    hypertrophy independent of the mechanical effect. The two accounts are not
    exclusive; they differ in what they nominate as the rate-limiting step and
    therefore in what a therapy should target.
  evidence:
  - reference: PMID:29760186
    reference_title: Hypertrophic cardiomyopathy mutations increase myofilament Ca(2+) buffering, alter intracellular Ca(2+) handling, and stimulate Ca(2+)-dependent signaling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Altered myofilament Ca2+ buffering is the primary initiator of signaling
      cascades, indicating that directly targeting myofilament Ca2+ sensitivity
      provides an attractive therapeutic approach in HCM.
    explanation: >-
      States the alternative primacy claim. The study expressed the TPM1 HCM
      variant D175N (alongside troponin variants) in isolated cardiomyocytes, so
      it speaks directly to the CMH3 thin-filament lesion.
- hypothesis_group_id: tpm1_variant_specific_phenotype_divergence
  hypothesis_label: Variant-specific molecular divergence between hypertrophic and dilated TPM1 phenotypes
  status: EMERGING
  description: >-
    TPM1 variants cause hypertrophic, dilated, restrictive, and noncompaction
    cardiomyopathy, and an emerging body of work proposes that the divergence is
    set by which physical property of tropomyosin the substitution perturbs.
    Paired analysis of E62Q (HCM) and E54K (DCM) attributes the hypertrophic
    phenotype to reduced molecular stiffness with a shift toward the closed
    regulatory state, and the dilated phenotype to a long-range allosteric change
    in troponin I mobile-domain binding. Whether this generalizes across the TPM1
    allelic series, and how it interacts with modifier genotype and sex, is not
    settled.
  evidence:
  - reference: PMID:39436707
    reference_title: Distinct mechanisms drive divergent phenotypes in hypertrophic and dilated cardiomyopathy-associated TPM1 variants.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Our objective was to develop a mechanistic explanation of diverging
      phenotypes in two TPM1 mutations, E62Q (HCM) and E54K (DCM).
    explanation: >-
      Frames the hypothesis. Evidence source is COMPUTATIONAL because the
      mechanistic explanation is delivered by simulation constrained by
      stem-cell-derived cardiomyocyte data.
  - reference: PMID:31643006
    reference_title: Cardiomyopathy-associated mutations in tropomyosin differently affect actin-myosin interaction at single-molecule and ensemble levels.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we found that the studied Tpm mutations differently affected the
      duration: the D175N mutation reduced it compared to WT Tpm, while the E180G
      mutation increased it.
    explanation: >-
      Shows that even two hypertrophic TPM1 alleles diverge at the
      single-molecule level, supporting variant specificity. PARTIAL because it
      does not itself connect the molecular divergence to a clinical phenotype.
pathophysiology:
- name: Alpha-Tropomyosin Thin Filament Regulatory Defect
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    TPM1 encodes alpha-tropomyosin, a rod-shaped coiled-coil dimer that polymerises
    head-to-tail along the actin thin filament and, in concert with the troponin
    complex, occupies the blocked, closed, or open azimuthal position that
    determines whether myosin can engage actin. Disease-associated missense
    substitutions are scattered along the molecule - in the N-terminal
    overlap/troponin T binding region (Arg21Leu, Gly3Arg, Glu62Gln, Gln68Arg), in
    the central period 4/5 region that contacts actin (Asp175Asn, Glu180Gly,
    Glu192Lys), and in the C-terminal region (Ser215Leu, Asp219Val, Asp254Gly) -
    and act by altering tropomyosin flexibility, its azimuthal positioning on
    actin, or its interactions with troponin, rather than by abolishing the
    protein. This is the primary cardiomyocyte insult of CMH3.
  genes:
  - preferred_term: TPM1
    term:
      id: hgnc:12010
      label: TPM1
  molecular_functions:
  - preferred_term: actin filament binding
    term:
      id: GO:0051015
      label: actin filament binding
    modifier: ABNORMAL
  - preferred_term: structural constituent of muscle
    term:
      id: GO:0008307
      label: structural constituent of muscle
    modifier: ABNORMAL
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: Myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  cellular_components:
  - preferred_term: sarcomere
    term:
      id: GO:0030017
      label: sarcomere
  - preferred_term: thin filament
    term:
      id: GO:0005865
      label: striated muscle thin filament
  biological_processes:
  - preferred_term: Regulation of muscle contraction
    term:
      id: GO:0006937
      label: regulation of muscle contraction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:8205619
    reference_title: "Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We demonstrate that missense mutations (Asp175Asn; Glu180Gly) in the
      alpha-tropomyosin gene cause familial hypertrophic cardiomyopathy (FHC)
      linked to chromosome 15q2.
    explanation: >-
      The founding CMH3 observation: alpha-tropomyosin missense variants at the
      15q locus cause familial hypertrophic cardiomyopathy.
  - reference: PMID:8205619
    reference_title: "Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Because alpha-tropomyosin and cardiac troponin T as well as beta myosin
      heavy chain mutations cause the same phenotype, we conclude that FHC is a
      disease of the sarcomere.
    explanation: >-
      Establishes that the TPM1 lesion belongs to the same sarcomeric-protein
      class as the thick-filament causes, which is why this node conforms to the
      generic primary-cardiomyocyte-insult node of the cardiomyopathy module.
  - reference: PMID:38223010
    reference_title: "A Novel TPM1 Mutation Causes Familial Hypertrophic Cardiomyopathy in an Indian Family: Genetic and Clinical Correlation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in TPM1 are known to cause hypertrophic cardiomyopathy, dilated
      cardiomyopathy and left ventricular non-compaction.
    explanation: >-
      Documents that the same gene underlies several cardiomyopathy phenotypes,
      the allelic-series context in which CMH3 sits.
  - reference: PMID:11603924
    reference_title: A familial hypertrophic cardiomyopathy alpha-tropomyosin mutation causes severe cardiac hypertrophy and death in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      This report demonstrates that mutations in alpha-tropomyosin can be
      severely disruptive of sarcomeric function, which consequently triggers a
      dramatic hypertrophic response that culminates in lethality.
    explanation: >-
      In vivo demonstration that an alpha-tropomyosin substitution is sufficient
      to initiate the hypertrophic cascade, establishing the TPM1 lesion as a
      causal trigger rather than a correlate. The allele modeled is Glu180Gly,
      one of the two founding CMH3 variants.
  - reference: PMID:11603924
    reference_title: A familial hypertrophic cardiomyopathy alpha-tropomyosin mutation causes severe cardiac hypertrophy and death in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      this mutation is an amino acid substitution at codon 180 (Glu180Gly) which
      occurs in a troponin T binding region
    explanation: >-
      Localizes the Glu180Gly lesion to the troponin T binding region,
      supporting the description of CMH3 variants as perturbing tropomyosin's
      regulatory partnerships rather than abolishing the protein.
  downstream:
  - target: Loss of Crossbridge Inhibition and Increased Myofilament Calcium Sensitivity
    causal_link_type: DIRECT
    hypothesis_groups:
    - tpm1_loss_of_crossbridge_inhibition
  - target: Increased Myofilament Calcium Buffering and Calcium-Dependent Signaling
    causal_link_type: DIRECT
    hypothesis_groups:
    - tpm1_calcium_buffering_signaling
  - target: Divergent Non-Hypertrophic Remodeling Phenotypes
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - tpm1_variant_specific_phenotype_divergence
    description: >-
      Allele-dependent branch: some TPM1 substitutions produce dilated,
      restrictive, or noncompaction remodeling instead of hypertrophy, and the
      determinants are not established.

- name: Loss of Crossbridge Inhibition and Increased Myofilament Calcium Sensitivity
  biological_scale: MOLECULAR
  role: amplifier
  description: >-
    Mutant alpha-tropomyosin is more flexible and sits less stably in the
    inhibitory (blocked/closed) position on actin, so the thin filament fails to
    keep myosin switched off. The measurable consequences are a left-shift in the
    calcium dependence of filament sliding, residual actomyosin activity at low
    calcium, and loss of the normal inhibition of sliding in relaxing conditions.
    Different alleles reach this end state by different routes - S215L and D219V
    principally by destabilizing the blocked state, E192K by permitting residual
    crossbridge activity even while overall calcium sensitivity falls - which is
    why calcium sensitivity alone is an incomplete description of the lesion.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  cellular_components:
  - preferred_term: striated muscle thin filament
    term:
      id: GO:0005865
      label: striated muscle thin filament
  biological_processes:
  - preferred_term: Regulation of muscle filament sliding
    term:
      id: GO:0032971
      label: regulation of muscle filament sliding
    modifier: ABNORMAL
  - preferred_term: Muscle filament sliding
    term:
      id: GO:0030049
      label: muscle filament sliding
    modifier: INCREASED
  evidence:
  - reference: PMID:36896133
    reference_title: Mechanisms of pathogenicity in the hypertrophic cardiomyopathy-associated TPM1 variant S215L.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Molecular dynamic simulations of tropomyosin on actin suggest that the
      S215L significantly destabilizes the blocked regulatory state while
      increasing flexibility of the tropomyosin chain.
    explanation: >-
      Direct structural statement of the regulatory-state destabilization that
      defines this node. Evidence source is COMPUTATIONAL because the claim comes
      from molecular-dynamics simulation.
  - reference: PMID:36896133
    reference_title: Mechanisms of pathogenicity in the hypertrophic cardiomyopathy-associated TPM1 variant S215L.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In vitro motility experiments with thin filaments containing TPM1 S215L
      revealed higher Ca2+ sensitivity compared with wild type.
    explanation: >-
      Experimental confirmation in reconstituted thin filaments that the
      simulated destabilization translates into increased myofilament calcium
      sensitivity.
  - reference: PMID:36613463
    reference_title: De Novo Asp219Val Mutation in Cardiac Tropomyosin Associated with Hypertrophic Cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The D219V mutation significantly increased the Ca2+ sensitivity of the
      sliding velocity of thin filaments over cardiac myosin in an in vitro
      motility assay and impaired the inhibition of the filament sliding at low
      Ca2+ concentration.
    explanation: >-
      Independent replication in a second TPM1 HCM allele, and the clearest
      single statement of the two components of the lesion - increased calcium
      sensitivity plus failure of inhibition at low calcium.
  - reference: PMID:34319370
    reference_title: Loss of crossbridge inhibition drives pathological cardiac hypertrophy in patients harboring the TPM1 E192K mutation.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Molecular dynamics revealed that E192K results in a more flexible TPM1
      molecule, which could affect its ability to regulate crossbridges.
    explanation: >-
      Shows increased tropomyosin flexibility as the shared physical
      consequence across variants, here for E192K.
  - reference: PMID:36158814
    reference_title: "Thin filament cardiomyopathies: A review of genetics, disease mechanisms, and emerging therapeutics."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      There is significant evidence that thin filament mutations contribute to
      dysregulation of Ca2+ within the sarcomere and may have a distinct
      pathomechanism of disease from cardiomyopathy associated with thick
      filament mutations.
    explanation: >-
      Places the TPM1 lesion in the broader thin-filament class and asserts that
      its pathomechanism is distinct from thick-filament HCM. Evidence source is
      OTHER because this is a narrative review.
  - reference: PMID:10900175
    reference_title: Effect of hypertrophic cardiomyopathy mutations in human cardiac muscle alpha-tropomyosin (Asp175Asn and Glu180Gly) on the regulatory properties of human cardiac troponin determined by in vitro motility assay.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      However, we observed increased Ca(2+)sensitivity of fraction of filaments
      motile using the mutant tropomyosin compared to wild-type
    explanation: >-
      Extends the calcium-sensitization finding to the two founding CMH3 alleles
      (Asp175Asn and Glu180Gly), measured in fully human reconstituted thin
      filaments with human cardiac troponin - the most isoform-faithful in vitro
      system available.
  - reference: PMID:11603924
    reference_title: A familial hypertrophic cardiomyopathy alpha-tropomyosin mutation causes severe cardiac hypertrophy and death in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      demonstrate dramatic functional differences in diastolic performance and
      increased sensitivity to calcium
    explanation: >-
      Confirms increased myofilament calcium sensitivity in an intact
      mammalian heart carrying a CMH3 allele, not only in reconstituted systems.
  downstream:
  - target: Cardiomyocyte Hypercontractility and Impaired Relaxation
    causal_link_type: DIRECT
    hypothesis_groups:
    - tpm1_loss_of_crossbridge_inhibition

- name: Increased Myofilament Calcium Buffering and Calcium-Dependent Signaling
  biological_scale: CELLULAR
  role: amplifier
  description: >-
    Because the mutant thin filament binds calcium more tightly, more of the
    cytosolic calcium transient is sequestered on the myofilaments. Diastolic
    calcium rises and reuptake slows; compensatory changes in sodium/calcium
    exchange, SERCA2 activity, and ryanodine-receptor leak follow, driven by
    CaMKII phosphorylation. The altered calcium environment chronically engages
    the calcineurin/NFAT and ERK pathways that transcriptionally program
    cardiomyocyte hypertrophy, and also creates a substrate for triggered
    arrhythmia.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Intracellular calcium ion homeostasis
    term:
      id: GO:0006874
      label: intracellular calcium ion homeostasis
    modifier: ABNORMAL
  - preferred_term: Calcineurin-NFAT signaling cascade
    term:
      id: GO:0033173
      label: calcineurin-NFAT signaling cascade
    modifier: INCREASED
  evidence:
  - reference: PMID:29760186
    reference_title: Hypertrophic cardiomyopathy mutations increase myofilament Ca(2+) buffering, alter intracellular Ca(2+) handling, and stimulate Ca(2+)-dependent signaling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      HCM mutations significantly lowered the Kd of Ca2+ binding, resulting in
      higher Ca2+ buffering of mutant cardiomyocytes.
    explanation: >-
      Quantifies the buffering change in cardiomyocytes expressing HCM
      thin-filament variants including the TPM1 allele D175N.
  - reference: PMID:29760186
    reference_title: Hypertrophic cardiomyopathy mutations increase myofilament Ca(2+) buffering, alter intracellular Ca(2+) handling, and stimulate Ca(2+)-dependent signaling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      coupled with a significant decrease in basal sarcomere length and slowed
      relaxation
    explanation: >-
      Links the buffering change to the diastolic phenotype: in the same
      sentence the authors report increased diastolic calcium and slowed calcium
      reuptake, and the quoted clause gives the mechanical consequence - shorter
      resting sarcomere length and slower relaxation. The quote starts
      mid-sentence because the preceding clause writes the calcium concentration
      in square brackets, which the reference validator normalizes away.
  - reference: PMID:29760186
    reference_title: Hypertrophic cardiomyopathy mutations increase myofilament Ca(2+) buffering, alter intracellular Ca(2+) handling, and stimulate Ca(2+)-dependent signaling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Altered Ca2+ homeostasis also increased signaling via both
      calcineurin/NFAT and extracellular signal-regulated kinase pathways.
    explanation: >-
      Provides the transcriptional link from the calcium abnormality to the
      hypertrophic program.
  - reference: PMID:32882290
    reference_title: The effect of tropomyosin variants on cardiomyocyte function and structure that underlie different clinical cardiomyopathy phenotypes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      All TPM1 variants result in reduced cardiomyocyte CaT amplitudes and loss
      of sarcomeric structures.
    explanation: >-
      Independent evidence that TPM1 variants disturb the cardiomyocyte calcium
      transient. PARTIAL because the variant panel spans HCM, DCM, and RCM
      alleles and the direction of the amplitude change differs from the
      buffering study, so it corroborates that calcium handling is perturbed
      without confirming the specific buffering mechanism.
  downstream:
  - target: Cardiomyocyte Hypertrophy with Myofiber Disarray and Interstitial Fibrosis
    causal_link_type: DIRECT
    hypothesis_groups:
    - tpm1_calcium_buffering_signaling
  - target: Arrhythmogenic Substrate and Sudden Cardiac Death
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Raised diastolic calcium, CaMKII-driven ryanodine-receptor leak, and
      altered repolarization contribute to triggered activity.

- name: Cardiomyocyte Hypercontractility and Impaired Relaxation
  biological_scale: CELLULAR
  role: amplifier
  description: >-
    At the level of the working myocyte the regulatory defect presents as
    hypercontractility with a relaxation deficit: three-dimensional engineered
    heart tissues carrying TPM1 HCM variants generate excess force, relax slowly,
    and show diastolic dysfunction, together with induction of hypertrophic gene
    markers and cellular hypertrophy. Patient-derived hiPSC-cardiomyocytes
    carrying the classic Asp175Asn allele reproduce the cellular phenotype with
    increased cell size and altered calcium handling and electrophysiology.
    Hypercontractility is the pathophysiological abnormality that
    myosin-inhibitor therapy is designed to reverse.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Cardiac muscle contraction
    term:
      id: GO:0060048
      label: cardiac muscle contraction
    modifier: INCREASED
  - preferred_term: Relaxation of cardiac muscle
    term:
      id: GO:0055119
      label: relaxation of cardiac muscle
    modifier: DECREASED
  evidence:
  - reference: PMID:36896133
    reference_title: Mechanisms of pathogenicity in the hypertrophic cardiomyopathy-associated TPM1 variant S215L.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Three-dimensional genetically engineered heart tissues expressing TPM1
      S215L exhibited hypercontractility, upregulation of hypertrophic gene
      markers, and diastolic dysfunction.
    explanation: >-
      Direct tissue-level demonstration of the three components of this node in a
      TPM1 HCM variant.
  - reference: PMID:34319370
    reference_title: Loss of crossbridge inhibition drives pathological cardiac hypertrophy in patients harboring the TPM1 E192K mutation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These tissues showed disease features similar to those of the patients,
      including cellular hypertrophy, hypercontractility, and diastolic
      dysfunction.
    explanation: >-
      Replicates the same triad in patient-derived engineered heart tissue and
      explicitly ties it to the donors' clinical features.
  - reference: PMID:27057166
    reference_title: Mutation-Specific Phenotypes in hiPSC-Derived Cardiomyocytes Carrying Either Myosin-Binding Protein C Or alpha-Tropomyosin Mutation for Hypertrophic Cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Both types of HCM-CMs displayed pathological phenotype of HCM but, more
      importantly, we found differences between CMs carrying either
      MYBPC3-Gln1061X or TPM1-Asp175Asn gene mutation in their cellular size,
      Ca(2+) handling, and electrophysiological properties, as well as their gene
      expression profiles.
    explanation: >-
      Shows that patient hiPSC-cardiomyocytes carrying the founding CMH3 allele
      reproduce a cellular HCM phenotype, and that it differs in detail from a
      thick-filament HCM phenotype.
  - reference: PMID:32871100
    reference_title: "Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiac muscle hypercontractility is a key pathophysiological abnormality
      in hypertrophic cardiomyopathy, and a major determinant of dynamic left
      ventricular outflow tract (LVOT) obstruction.
    explanation: >-
      Establishes hypercontractility as the clinically actionable abnormality and
      as the driver of outflow obstruction, linking this node to the treatment
      section.
  downstream:
  - target: Cardiomyocyte Hypertrophy with Myofiber Disarray and Interstitial Fibrosis
    causal_link_type: DIRECT
    hypothesis_groups:
    - tpm1_loss_of_crossbridge_inhibition
  - target: Diastolic Dysfunction and Left Ventricular Outflow Tract Obstruction
    causal_link_type: DIRECT

- name: Cardiomyocyte Hypertrophy with Myofiber Disarray and Interstitial Fibrosis
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
  biological_scale: TISSUE
  role: central_effector
  description: >-
    Sustained hypercontractility and calcium-dependent hypertrophic signaling
    remodel the myocardium into the classic hypertrophic pattern: myocyte
    hypertrophy, loss of the normal parallel myofibre architecture (disarray),
    and replacement/interstitial fibrosis, producing wall thickening with a small
    cavity. Histology in TPM1-mutation hearts is indistinguishable from that of
    other sarcomeric causes, so the node is a faithful specialization of the
    generic ventricular-remodeling node rather than a TPM1-specific pathology.
    Human cardiac biopsies carrying TPM1 variants show loss of sarcomeric
    structure.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: Cardiac Fibroblast
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  locations:
  - preferred_term: interventricular septum
    term:
      id: UBERON:0002094
      label: interventricular septum
  - preferred_term: left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  biological_processes:
  - preferred_term: Cardiac muscle hypertrophy in response to stress
    term:
      id: GO:0014898
      label: cardiac muscle hypertrophy in response to stress
    modifier: INCREASED
  - preferred_term: Sarcomere organization
    term:
      id: GO:0045214
      label: sarcomere organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:9060904
    reference_title: Clinical features of hypertrophic cardiomyopathy caused by mutation of a "hot spot" in the alpha-tropomyosin gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The Asp175Asn mutation caused cardiac histopathologic findings of myocyte
      hypertrophy, disarray and replacement fibrosis.
    explanation: >-
      Human histopathology in TPM1-mutation carriers establishing all three
      components of this node.
  - reference: PMID:9060904
    reference_title: Clinical features of hypertrophic cardiomyopathy caused by mutation of a "hot spot" in the alpha-tropomyosin gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On cardiac histopathologic study, defects in this sarcomere thin filament
      component are indistinguishable from other genetic etiologies of
      hypertrophic cardiomyopathy.
    explanation: >-
      Justifies modeling this node as a conformer of the generic cardiomyopathy
      remodeling module rather than as a TPM1-specific tissue lesion.
  - reference: PMID:32882290
    reference_title: The effect of tropomyosin variants on cardiomyocyte function and structure that underlie different clinical cardiomyopathy phenotypes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Human cardiac biopsies with TPM1 variants revealed loss of sarcomeric
      structures.
    explanation: >-
      Confirms structural sarcomeric disorganization in human myocardium carrying
      TPM1 variants.
  - reference: PMID:11603924
    reference_title: A familial hypertrophic cardiomyopathy alpha-tropomyosin mutation causes severe cardiac hypertrophy and death in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Histological analysis shows that initial pathological changes, which
      include ventricular concentric hypertrophy, fibrosis and atrial
      enlargement, are detected within 1 month.
    explanation: >-
      In vivo confirmation that a CMH3 allele produces the
      hypertrophy-plus-fibrosis remodeling pattern of this node, and that it
      appears early. Note
      the mouse geometry is concentric rather than the asymmetric septal pattern
      typical of human disease.
  downstream:
  - target: Diastolic Dysfunction and Left Ventricular Outflow Tract Obstruction
    causal_link_type: DIRECT
  - target: Arrhythmogenic Substrate and Sudden Cardiac Death
    causal_link_type: DIRECT

- name: Diastolic Dysfunction and Left Ventricular Outflow Tract Obstruction
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Progressive Contractile Dysfunction"
  biological_scale: ORGANISM
  role: effector
  description: >-
    The stiffened, hypertrophied, fibrotic ventricle fills poorly, and when
    hypertrophy is asymmetric and septal it can also obstruct the left
    ventricular outflow tract dynamically. The clinical result is exertional
    dyspnoea, chest pain, and reduced exercise capacity with preserved or
    supranormal ejection fraction. Thin-filament HCM as a class tends to produce
    relatively less hypertrophy and less outflow obstruction than thick-filament
    HCM while carrying more heart-failure morbidity, so the obstructive
    presentation should not be assumed in a TPM1 carrier.
  biological_processes:
  - preferred_term: Relaxation of cardiac muscle
    term:
      id: GO:0055119
      label: relaxation of cardiac muscle
    modifier: DECREASED
  - preferred_term: Heart contraction
    term:
      id: GO:0060047
      label: heart contraction
    modifier: ABNORMAL
  locations:
  - preferred_term: left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  evidence:
  - reference: PMID:32217077
    reference_title: "Mutation-specific pathology and treatment of hypertrophic cardiomyopathy in patients, mouse models and human engineered heart tissue."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Hypertrophic cardiomyopathy (HCM) is the most common inherited
      cardiomyopathy and is characterized by asymmetric left ventricular
      hypertrophy and diastolic dysfunction, and a frequent cause of sudden
      cardiac death at young age.
    explanation: >-
      States the asymmetric-hypertrophy-plus-diastolic-dysfunction phenotype that
      this node represents. Evidence source is OTHER because this is a review.
  - reference: PMID:36158814
    reference_title: "Thin filament cardiomyopathies: A review of genetics, disease mechanisms, and emerging therapeutics."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A number of distinct clinical findings appear to be correlated with
      thin-filament mutations: greater degrees of restrictive cardiomyopathy and
      relatively less left ventricular (LV) hypertrophy and LV outflow tract
      obstruction than that seen with thick filament mutations, increased
      morbidity associated with heart failure, increased arrhythmia burden and
      potentially higher mortality.
    explanation: >-
      The key CMH3-specific qualifier on this node: thin-filament HCM skews away
      from obstruction and toward restrictive physiology, heart failure, and
      arrhythmia.
  downstream:
  - target: Progressive Heart Failure
    causal_link_type: DIRECT

- name: Arrhythmogenic Substrate and Sudden Cardiac Death
  biological_scale: ORGANISM
  role: consequence
  description: >-
    Myofibre disarray, interstitial and replacement fibrosis, and abnormal
    calcium handling together create a substrate for reentrant and triggered
    ventricular arrhythmia. Sudden cardiac death is the outcome that dominates
    risk stratification in CMH3, and several TPM1 pedigrees have been ascertained
    through a sudden death. Risk is markedly allele-dependent: sudden-death risk
    was low in most p.Arg21Leu carriers, whereas other alleles - and digenic
    thin-plus-thick-filament genotypes - have been associated with severe disease
    and sudden death.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Regulation of heart rate by cardiac conduction
    term:
      id: GO:0086091
      label: regulation of heart rate by cardiac conduction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:36613463
    reference_title: De Novo Asp219Val Mutation in Cardiac Tropomyosin Associated with Hypertrophic Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypertrophic cardiomyopathy (HCM), caused by mutations in thin filament
      proteins, manifests as moderate cardiac hypertrophy and is associated with
      sudden cardiac death (SCD).
    explanation: >-
      States the thin-filament HCM phenotype of moderate hypertrophy with sudden
      death risk, in a report of a de novo TPM1 variant identified in a sudden
      death victim.
  - reference: PMID:38874371
    reference_title: Identification of a novel likely pathogenic TPM1 variant linked to hypertrophic cardiomyopathy in a family with sudden cardiac death.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The identification of a novel TPM1 variant in a family with HCM and SCD
      underscores the critical role of genetic screening in at-risk families.
    explanation: >-
      Documents a TPM1 HCM pedigree ascertained through sudden cardiac death.
  - reference: PMID:33642254
    reference_title: "Genotype-phenotype correlations in hypertrophic cardiomyopathy: a multicenter study in Portugal and Spain of the TPM1 p.Arg21Leu variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Calculated HCM sudden death risk was low in 34 carriers (77.5%),
      intermediated in 8 (18%), and high in only 2 (4.5%).
    explanation: >-
      Shows that sudden-death risk in the largest single-variant TPM1 series was
      low for most carriers. PARTIAL because it establishes allele-dependent
      low risk rather than supporting the arrhythmogenic mechanism itself.
  - reference: PMID:12651045
    reference_title: Variable clinical manifestation of a novel missense mutation in the alpha-tropomyosin (TPM1) gene in familial hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Twelve family members presented clinical features of HCM, five of whom
      died at young age, while others had only mild clinical features.
    explanation: >-
      The counterweight to the favourable p.Arg21Leu series: a single TPM1
      kindred (Glu62Gln) with five young deaths, establishing that some CMH3
      alleles carry high sudden-death risk.
  - reference: PMID:7898523
    reference_title: Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These mutations are characterized by relatively mild and sometimes
      subclinical hypertrophy but a high incidence of sudden death.
    explanation: >-
      The classic mild-hypertrophy-high-sudden-death description. PARTIAL
      because in the source sentence this characterization is attached to the
      cardiac troponin T mutations analysed alongside alpha-tropomyosin, so it
      describes thin-filament HCM broadly rather than TPM1 specifically.

- name: Progressive Heart Failure
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure"
  biological_scale: ORGANISM
  role: consequence
  description: >-
    A minority of CMH3 patients progress to symptomatic heart failure, and
    thin-filament HCM as a class carries higher heart-failure morbidity than
    thick-filament HCM. Outcome nonetheless remains strongly allele-dependent:
    survival free of cardiovascular death or transplant was 87.5% at 50 years in
    the p.Arg21Leu founder series, and near-normal life expectancy was reported
    for Asp175Asn.
  biological_processes:
  - preferred_term: Heart contraction
    term:
      id: GO:0060047
      label: heart contraction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:33642254
    reference_title: "Genotype-phenotype correlations in hypertrophic cardiomyopathy: a multicenter study in Portugal and Spain of the TPM1 p.Arg21Leu variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Survival free of cardiovascular death or heart transplant was 87.5% at 50
      years.
    explanation: >-
      Quantifies transplant-free survival, the clinical endpoint of this node,
      for the best-characterized TPM1 HCM allele.
  - reference: PMID:9060904
    reference_title: Clinical features of hypertrophic cardiomyopathy caused by mutation of a "hot spot" in the alpha-tropomyosin gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast, prognosis reflected genotype; near normal life expectancy is
      found in hypertrophic cardiomyopathy caused by the alpha-tropomyosin
      mutation Asp175Asn.
    explanation: >-
      Establishes that prognosis in CMH3 is genotype-dependent and can be
      favourable, tempering the generic heart-failure endpoint.

- name: Divergent Non-Hypertrophic Remodeling Phenotypes
  biological_scale: TISSUE
  role: modifier
  description: >-
    Not every TPM1 variant produces hypertrophy. The same gene causes dilated,
    restrictive, and left ventricular noncompaction cardiomyopathy, and
    compound-heterozygous TPM1 genotypes have produced restrictive disease in a
    child whose singly heterozygous relatives had diastolic dysfunction and HCM.
    Paired mechanistic study of E62Q (hypertrophic) and E54K (dilated) attributes
    the divergence to which physical property of tropomyosin the substitution
    perturbs. This node is included because it constrains how a TPM1 finding may
    be interpreted clinically, not because it is part of the CMH3 causal chain.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:39436707
    reference_title: Distinct mechanisms drive divergent phenotypes in hypertrophic and dilated cardiomyopathy-associated TPM1 variants.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      In E62Q, increased calcium sensitivity and hypercontractility was explained
      most accurately by a reduction in effective molecular stiffness of
      tropomyosin and alterations in its interactions with the actin thin
      filament that favor the "closed" regulatory state.
    explanation: >-
      Gives the proposed molecular basis of the hypertrophic branch, against
      which the dilated branch is contrasted in the same study.
  - reference: PMID:39436707
    reference_title: Distinct mechanisms drive divergent phenotypes in hypertrophic and dilated cardiomyopathy-associated TPM1 variants.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      By contrast, the E54K mutation appeared to act via long-range allosteric
      interactions to increase the association rate of the C-terminal troponin I
      mobile domain to tropomyosin/actin.
    explanation: >-
      The contrasting dilated-phenotype mechanism, establishing that the
      divergence has a molecular explanation rather than being purely stochastic.
  - reference: PMID:32882290
    reference_title: The effect of tropomyosin variants on cardiomyocyte function and structure that underlie different clinical cardiomyopathy phenotypes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a large family with DCM carrying a recently identified TPM1
      gene variant (T201M) and a child with RCM with compound heterozygote TPM1
      variants (E62Q and M281T) whose family members carrying single variants
      show diastolic dysfunction and HCM.
    explanation: >-
      Shows the hypertrophic, restrictive, and dilated expressions of TPM1
      variation coexisting within families, including allele-dose dependence.
  - reference: CGGV:assertion_1173d239-23cf-4c9c-9ea5-f95d9356e6c7-2025-04-04T160000.000Z
    reference_title: "TPM1 / dilated cardiomyopathy (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      TPM1 | HGNC:12010 | dilated cardiomyopathy | MONDO:0005021 | AD | Moderate
    explanation: >-
      ClinGen curates a separate, weaker (Moderate) TPM1-dilated cardiomyopathy
      relationship alongside the Definitive hypertrophic one, confirming the
      allelic series is recognized at the gene-disease-validity level.
phenotypes:
- name: Hypertrophic Cardiomyopathy
  category: Cardiovascular
  description: >-
    Unexplained left ventricular hypertrophy in the absence of abnormal loading
    conditions, the defining phenotype of CMH3.
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  frequency: OBLIGATE
  diagnostic: true
  evidence:
  - reference: PMID:8205619
    reference_title: "Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We demonstrate that missense mutations (Asp175Asn; Glu180Gly) in the
      alpha-tropomyosin gene cause familial hypertrophic cardiomyopathy (FHC)
      linked to chromosome 15q2.
    explanation: >-
      Establishes hypertrophic cardiomyopathy as the phenotype caused by TPM1
      variants. The frequency is OBLIGATE because it is the defining feature of
      the disease entity, not an associated finding.
- name: Left Ventricular Hypertrophy
  category: Cardiovascular
  description: >-
    Increased left ventricular wall thickness. Severity and distribution vary
    considerably even between families carrying the same TPM1 allele, and
    thin-filament HCM tends to produce relatively less hypertrophy than
    thick-filament HCM.
  phenotype_term:
    preferred_term: Left ventricular hypertrophy
    term:
      id: HP:0001712
      label: Left ventricular hypertrophy
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:9060904
    reference_title: Clinical features of hypertrophic cardiomyopathy caused by mutation of a "hot spot" in the alpha-tropomyosin gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The severity and distribution of left ventricular hypertrophy varied
      considerably in affected members from the three families
    explanation: >-
      Documents left ventricular hypertrophy in all three TPM1 Asp175Asn kindreds
      and its variable severity and distribution. Frequency VERY_FREQUENT because
      hypertrophy was present across affected members of every reported kindred
      while penetrance is incomplete.
  - reference: PMID:38874371
    reference_title: Identification of a novel likely pathogenic TPM1 variant linked to hypertrophic cardiomyopathy in a family with sudden cardiac death.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypertrophic cardiomyopathy (HCM) is an autosomal dominant genetic cardiac
      disorder characterized by unexplained left ventricular hypertrophy.
    explanation: >-
      Confirms unexplained left ventricular hypertrophy as the cardinal finding,
      in a TPM1-variant pedigree report.
- name: Asymmetric Septal Hypertrophy
  category: Cardiovascular
  description: >-
    Disproportionate thickening of the interventricular septum relative to the
    free wall, the classic HCM morphology and the substrate for dynamic outflow
    obstruction.
  phenotype_term:
    preferred_term: Asymmetric septal hypertrophy
    term:
      id: HP:0001670
      label: Asymmetric septal hypertrophy
  evidence:
  - reference: PMID:32217077
    reference_title: "Mutation-specific pathology and treatment of hypertrophic cardiomyopathy in patients, mouse models and human engineered heart tissue."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Hypertrophic cardiomyopathy (HCM) is the most common inherited
      cardiomyopathy and is characterized by asymmetric left ventricular
      hypertrophy and diastolic dysfunction, and a frequent cause of sudden
      cardiac death at young age.
    explanation: >-
      Supports asymmetric hypertrophy as characteristic of HCM. PARTIAL because
      the statement is HCM-wide rather than TPM1-specific; the TPM1 Asp175Asn
      kindreds showed anterior, posterior, and free-wall predominant patterns.
- name: Myocardial Sarcomeric Disarray
  category: Cardiovascular
  description: >-
    Loss of the normal parallel alignment of cardiomyocytes and their sarcomeres,
    with cellular hypertrophy - the histological hallmark of sarcomeric HCM,
    documented in TPM1-mutation hearts.
  phenotype_term:
    preferred_term: Myocardial sarcomeric disarray
    term:
      id: HP:0031333
      label: Myocardial sarcomeric disarray
  evidence:
  - reference: PMID:9060904
    reference_title: Clinical features of hypertrophic cardiomyopathy caused by mutation of a "hot spot" in the alpha-tropomyosin gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The Asp175Asn mutation caused cardiac histopathologic findings of myocyte
      hypertrophy, disarray and replacement fibrosis.
    explanation: >-
      Direct histopathological documentation of myocyte disarray in hearts
      carrying a TPM1 HCM variant.
- name: Myocardial Fibrosis
  category: Cardiovascular
  description: >-
    Replacement and interstitial fibrosis of the hypertrophied myocardium,
    contributing to diastolic stiffness and to the arrhythmogenic substrate.
  phenotype_term:
    preferred_term: Myocardial fibrosis
    term:
      id: HP:0001685
      label: Myocardial fibrosis
  evidence:
  - reference: PMID:9060904
    reference_title: Clinical features of hypertrophic cardiomyopathy caused by mutation of a "hot spot" in the alpha-tropomyosin gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The Asp175Asn mutation caused cardiac histopathologic findings of myocyte
      hypertrophy, disarray and replacement fibrosis.
    explanation: >-
      Documents replacement fibrosis on histopathology in TPM1 Asp175Asn
      carriers.
- name: Left Ventricular Diastolic Dysfunction
  category: Cardiovascular
  description: >-
    Impaired ventricular relaxation and filling, present at the level of
    engineered heart tissue carrying TPM1 variants and clinically in carriers.
  phenotype_term:
    preferred_term: Left ventricular diastolic dysfunction
    term:
      id: HP:0025168
      label: Left ventricular diastolic dysfunction
  evidence:
  - reference: PMID:34319370
    reference_title: Loss of crossbridge inhibition drives pathological cardiac hypertrophy in patients harboring the TPM1 E192K mutation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These tissues showed disease features similar to those of the patients,
      including cellular hypertrophy, hypercontractility, and diastolic
      dysfunction.
    explanation: >-
      Diastolic dysfunction reproduced in patient-derived engineered heart tissue
      and explicitly matched to the donors' clinical phenotype.
  - reference: PMID:32882290
    reference_title: The effect of tropomyosin variants on cardiomyocyte function and structure that underlie different clinical cardiomyopathy phenotypes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      whose family members carrying single variants show diastolic dysfunction
      and HCM
    explanation: >-
      Documents diastolic dysfunction in heterozygous TPM1 variant carriers in a
      clinical family study.
- name: Left Ventricular Outflow Tract Obstruction
  category: Cardiovascular
  description: >-
    Dynamic obstruction of the left ventricular outflow tract by the hypertrophied
    septum with systolic anterior motion of the mitral valve. Reported less often
    in thin-filament than in thick-filament HCM, so it should not be assumed in a
    TPM1 carrier.
  phenotype_term:
    preferred_term: Left ventricular outflow tract obstruction
    term:
      id: HP:0032092
      label: Left ventricular outflow tract obstruction
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:36158814
    reference_title: "Thin filament cardiomyopathies: A review of genetics, disease mechanisms, and emerging therapeutics."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      greater degrees of restrictive cardiomyopathy and relatively less left
      ventricular (LV) hypertrophy and LV outflow tract obstruction than that
      seen with thick filament mutations
    explanation: >-
      Establishes that outflow obstruction occurs but is less frequent in
      thin-filament HCM. The OCCASIONAL band is a qualitative mapping of "less
      than thick-filament HCM" (where obstruction affects roughly 60% of
      patients) and is marked PARTIAL because no TPM1-specific rate is reported.
- name: Sudden Cardiac Death
  category: Cardiovascular
  description: >-
    Sudden death from ventricular arrhythmia, the outcome that dominates risk
    stratification. Several TPM1 pedigrees have been ascertained through a sudden
    death, but calculated risk was low in the majority of carriers of the
    best-characterized allele.
  phenotype_term:
    preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: PMID:38874371
    reference_title: Identification of a novel likely pathogenic TPM1 variant linked to hypertrophic cardiomyopathy in a family with sudden cardiac death.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this study, we aimed to characterize the clinical and molecular
      phenotype of HCM in an Iranian pedigree with SCD.
    explanation: >-
      A TPM1 HCM pedigree ascertained through sudden cardiac death.
  - reference: PMID:38223010
    reference_title: "A Novel TPM1 Mutation Causes Familial Hypertrophic Cardiomyopathy in an Indian Family: Genetic and Clinical Correlation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, some high-risk mutations causing sudden cardiac death are also
      known in this gene.
    explanation: >-
      States that high-risk sudden-death alleles exist within TPM1, the basis for
      allele-specific risk stratification.
  - reference: PMID:12651045
    reference_title: Variable clinical manifestation of a novel missense mutation in the alpha-tropomyosin (TPM1) gene in familial hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical data suggest a malignant phenotype at young age with a
      variable clinical manifestation and penetrance at older age.
    explanation: >-
      Documents a malignant young-onset TPM1 sudden-death phenotype coexisting
      with mild disease in older relatives of the same family.
- name: Congestive Heart Failure
  category: Cardiovascular
  description: >-
    Symptomatic heart failure, a less common but important endpoint; thin-filament
    HCM carries higher heart-failure morbidity than thick-filament HCM.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:38874371
    reference_title: Identification of a novel likely pathogenic TPM1 variant linked to hypertrophic cardiomyopathy in a family with sudden cardiac death.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It can cause a wide spectrum of clinical manifestations, ranging from
      asymptomatic to heart failure and sudden cardiac death (SCD).
    explanation: >-
      Places heart failure on the CMH3 clinical spectrum. The OCCASIONAL band
      reflects that most carriers in the largest series remained free of
      cardiovascular death or transplant at 50 years.
  - reference: PMID:36158814
    reference_title: "Thin filament cardiomyopathies: A review of genetics, disease mechanisms, and emerging therapeutics."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      increased morbidity associated with heart failure, increased arrhythmia
      burden and potentially higher mortality
    explanation: >-
      Supports elevated heart-failure morbidity as a thin-filament class feature.
      PARTIAL because the claim is class-level rather than TPM1-specific.
- name: Restrictive Cardiomyopathy
  category: Cardiovascular
  description: >-
    A restrictive filling phenotype occurs in part of the TPM1 spectrum,
    particularly with compound-heterozygous genotypes, and thin-filament
    cardiomyopathy as a class shows more restrictive physiology than
    thick-filament disease.
  phenotype_term:
    preferred_term: Restrictive cardiomyopathy
    term:
      id: HP:0001723
      label: Restrictive cardiomyopathy
  frequency: VERY_RARE
  evidence:
  - reference: PMID:32882290
    reference_title: The effect of tropomyosin variants on cardiomyocyte function and structure that underlie different clinical cardiomyopathy phenotypes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a child with RCM with compound heterozygote TPM1 variants (E62Q and M281T)
    explanation: >-
      Documents restrictive cardiomyopathy in a TPM1 compound heterozygote whose
      singly heterozygous relatives had HCM, i.e. an allele-dose-dependent
      restrictive expression within a CMH3 family.
- name: Exercise Intolerance
  category: Cardiovascular
  description: >-
    Reduced exercise capacity from impaired diastolic filling with or without
    outflow obstruction, the symptom domain that responds to myosin-inhibitor
    therapy in obstructive disease.
  phenotype_term:
    preferred_term: Exercise intolerance
    term:
      id: HP:0003546
      label: Exercise intolerance
  evidence:
  - reference: PMID:32871100
    reference_title: "Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment with mavacamten improved exercise capacity, LVOT obstruction,
      NYHA functional class, and health status in patients with obstructive
      hypertrophic cardiomyopathy.
    explanation: >-
      Establishes reduced exercise capacity as a treatable clinical feature of
      obstructive HCM. PARTIAL because the trial enrolled obstructive HCM
      generally rather than genotyped TPM1 carriers.
- category: Cardiovascular
  name: Non-Sustained Ventricular Tachycardia
  description: >-
    Non-sustained ventricular arrhythmia is one of the features that marks
    elevated sudden-death risk in thin-filament hypertrophic cardiomyopathy, the
    class to which TPM1 disease belongs, and it is a component of the
    conventional risk-stratification tools. Its status in this genotype is
    genuinely unsettled rather than simply unmeasured - see the arrhythmic-risk
    knowledge gap - because the one prospective thin-filament cohort with
    follow-up recorded no malignant arrhythmic events at all.
  phenotype_term:
    preferred_term: Non-sustained ventricular tachycardia
    term:
      id: HP:0004756
      label: Ventricular tachycardia
  notes: >-
    Frequency deliberately omitted. Cohort percentages for NSVT in thin-filament
    HCM circulate in the literature but are not present in any abstract cached
    for this entry, and the direction of the effect is disputed between cohorts.
    HPO has no non-sustained-VT term, so the general term carries a narrower
    preferred_term.
  evidence:
  - reference: PMID:36158814
    reference_title: "Thin filament cardiomyopathies: A review of genetics, disease mechanisms, and emerging therapeutics."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      high risk of SCD with positive family history, non-sustained ventricular
      arrythmias and abnormal
    explanation: >-
      Places non-sustained ventricular arrhythmia among the risk markers in
      thin-filament HCM. The snippet is a mid-sentence span because the cached
      PDF renders "affected by thin filament" with typographic ligatures that
      break exact substring matching. PARTIAL because this is a narrative review of the
      thin-filament class rather than a TPM1-specific measurement, and because
      the same class's prospective cohort data conflict with it.
- category: Cardiovascular
  name: Syncope
  description: >-
    Syncope of presumed arrhythmic origin is one of the established indications
    for defibrillator implantation in hypertrophic cardiomyopathy, which is what
    gives it weight in this entry beyond symptom burden - it feeds directly into
    the risk stratification the ICD treatment depends on.
  phenotype_term:
    preferred_term: Syncope
    term:
      id: HP:0001279
      label: Syncope
  notes: >-
    Frequency deliberately omitted - no cached source reports a syncope rate in
    TPM1 or thin-filament HCM.
  evidence:
  - reference: PMID:36158814
    reference_title: "Thin filament cardiomyopathies: A review of genetics, disease mechanisms, and emerging therapeutics."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      a history of syncope due to
      arrhythmia, LV apical aneurysm or LV systolic dysfunction
    explanation: >-
      Places arrhythmic syncope among the ICD indications. PARTIAL because it is
      a general HCM recommendation restated in a thin-filament review, not a
      TPM1-specific observation.
- category: Cardiovascular
  name: Abnormal Electrocardiogram
  description: >-
    The earliest detectable abnormality, and the reason cascade surveillance of
    genotype-positive relatives is worth doing at all. In a prospective cohort of
    sarcomere-variant carriers followed to diagnosis, 72.3% had an abnormal ECG
    at the time of HCM diagnosis and 54.2% had one BEFORE they met diagnostic
    criteria - a median 4.4 years before. An abnormal ECG in a genotype-positive
    relative is therefore not an incidental finding but the strongest available
    predictor of subsequent conversion to overt disease.
  phenotype_term:
    preferred_term: Abnormal EKG
    term:
      id: HP:0003115
      label: Abnormal EKG
  evidence:
  - reference: PMID:32731933
    reference_title: "Penetrance of Hypertrophic Cardiomyopathy in Sarcomere Protein Mutation Carriers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of these, 45 (54.2%) of 83 had an abnormal ECG before fulfilling the
      diagnostic criteria and this was first documented a median 4.4 years
    explanation: >-
      Establishes ECG abnormality as an antecedent of overt HCM rather than a
      concomitant of it, which is the empirical justification for the serial ECG
      surveillance this entry curates as cascade testing.
  notes: >-
    The cohort is sarcomere-variant carriers across genes, of whom TPM1 carriers
    were 3.2% (9 individuals), so this is class-level rather than
    TPM1-specific evidence. It is curated at SUPPORT rather than PARTIAL because
    the claim being made - that ECG change precedes diagnosis in sarcomeric HCM -
    is exactly what the cohort measured.
genetic:
- name: TPM1
  gene_term:
    preferred_term: TPM1
    term:
      id: hgnc:12010
      label: TPM1
  relationship_type: CAUSATIVE
  frequency: >-
    Minority cause of hypertrophic cardiomyopathy - about 3% of familial cases in
    the founding referral-centre survey, under 1% in more recent series.
  case_fractions:
  - population: Familial HCM referral-centre cohort (Watkins et al.)
    case_fraction_percent: 3.0
    notes: >-
      Historical estimate from the first systematic screen of alpha-tropomyosin
      in HCM probands.
    evidence:
    - reference: PMID:7898523
      reference_title: Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Mutations in alpha-tropomyosin are a rare cause of familial hypertrophic
        cardiomyopathy, accounting for approximately 3 percent of cases.
      explanation: >-
        Direct quantitative statement of the TPM1 case fraction in familial HCM.
  - population: Iberian inherited-cardiac-disease cohort, p.Arg21Leu variant only
    case_fraction_percent: 0.61
    cohort_size: 4099
    notes: >-
      Single-variant fraction (p.Arg21Leu) among HCM cases in a 10,561-proband
      inherited-heart-disease series; reflects a regional founder effect in
      Galicia, Extremadura, and northern Portugal rather than a general TPM1
      rate.
    evidence:
    - reference: PMID:33642254
      reference_title: "Genotype-phenotype correlations in hypertrophic cardiomyopathy: a multicenter study in Portugal and Spain of the TPM1 p.Arg21Leu variant."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The TPM1 p.Arg21Leu variant was identified in 25/4099 (0.61%) HCM-cases,
        and was absent in 6462 control individuals with other inherited cardiac
        phenotypes (P<.0001).
      explanation: >-
        Gives the case fraction and cohort size for the founder variant, with
        case-control contrast.
  evidence:
  - reference: PMID:32731933
    reference_title: "Penetrance of Hypertrophic Cardiomyopathy in Sarcomere Protein Mutation Carriers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At 15 years follow-up, estimated HCM penetrance by causal gene was as
      follows: MYBPC3 43% (95% CI: 32% to 57%), MYH7 66% (95% CI: 47% to 83%),
      TNNI3 17% (95% CI: 7% to 39%), TNNT2 50% (95% CI: 30% to 74%), TPM1 42%
      (95% CI: 11% to 92%)
    explanation: >-
      The only gene-specific penetrance estimate available for TPM1: 42% at 15
      years. It is quoted with its full confidence interval and alongside the
      other genes deliberately, because the interval - 11% to 92% - overlaps
      every other gene in the table and the estimate rests on 9 carriers across
      3 families. PARTIAL for that reason: the point estimate is not
      distinguishable from the other sarcomere genes and must not be counselled
      as though it were a TPM1-specific figure. Quoting the bare 42% without the
      interval would be worse than omitting it.
  - reference: PMID:32731933
    reference_title: "Penetrance of Hypertrophic Cardiomyopathy in Sarcomere Protein Mutation Carriers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Overall, HCM penetrance at 15 years follow-up was 46%
    explanation: >-
      The all-gene benchmark the TPM1 estimate should be read against; the
      reported interval for this figure is 38% to 54%, quoted here in the
      explanation rather than the snippet because the validator normalises
      square-bracketed text. TPM1's 42% sits inside that interval, which is the
      clearest way to see that the gene-specific figure carries no information
      beyond the cohort average.
  - reference: CGGV:assertion_32e7ed58-ee49-4719-b48e-7fad58012319-2023-12-18T170000.000Z
    reference_title: "TPM1 / hypertrophic cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      TPM1 | HGNC:12010 | hypertrophic cardiomyopathy | MONDO:0005045 | AD |
      Definitive
    explanation: >-
      ClinGen classifies the TPM1-hypertrophic cardiomyopathy gene-disease
      relationship as Definitive.
  - reference: PMID:8205619
    reference_title: "Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We demonstrate that missense mutations (Asp175Asn; Glu180Gly) in the
      alpha-tropomyosin gene cause familial hypertrophic cardiomyopathy (FHC)
      linked to chromosome 15q2.
    explanation: >-
      The original gene-disease assertion establishing TPM1 as causative for
      CMH3.
  - reference: PMID:38223010
    reference_title: "A Novel TPM1 Mutation Causes Familial Hypertrophic Cardiomyopathy in an Indian Family: Genetic and Clinical Correlation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in TPM1 causing hypertrophic cardiomyopathy are < 1%.
    explanation: >-
      Contemporary estimate of the TPM1 contribution to HCM, lower than the
      historical 3% figure from referral-centre ascertainment.
  - reference: PMID:12651045
    reference_title: Variable clinical manifestation of a novel missense mutation in the alpha-tropomyosin (TPM1) gene in familial hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The Glu62Gln mutation is the sixth TPM1 mutation identified as the cause of
      FHC, indicating that mutations in this gene are very rare.
    explanation: >-
      Independent statement of TPM1 rarity as an HCM cause, and a count of the
      known allelic series at the time of report.
  notes: >-
    The Glu62Gln allele is a useful anchor because it has both a human clinical
    pedigree (PMID:12651045, twelve affected members, five young deaths) and a
    full engineered-heart-tissue mechanistic characterization (PMID:39436707) -
    a rare combination in this gene.

    Reported CMH3 alleles are missense and distributed across the molecule rather
    than confined to a single hotspot, although codon 175/180 (period 4/5) and
    codon 21 (N-terminal) recur. Alleles cited in this entry with human
    genotype-phenotype data: Asp175Asn, Glu180Gly, Arg21Leu, Ser215Leu, Gln68Arg,
    Asp254Gly, Gly3Arg (homozygous), and Glu62Gln; alleles characterized
    principally in vitro or in silico: Glu192Lys, Asp219Val.
- name: MYH7 (digenic modifier)
  gene_term:
    preferred_term: MYH7
    term:
      id: hgnc:7577
      label: MYH7
  relationship_type: COOPERATING
  notes: >-
    Coexistence of a thin-filament TPM1 variant with thick-filament MYH7 variants
    has been reported to produce more severe hypertrophy than the TPM1 variant
    alone, and 18% of carriers in the p.Arg21Leu founder series carried an
    additional sarcomere-gene variant. Multi-variant genotype is therefore a
    relevant modifier when interpreting a TPM1 finding.

    This entry deliberately does NOT bind a digenic inheritance term
    (HP:0010984) and is not a member of the Digenic and Oligogenic Disorders
    grouping. A TPM1 variant alone causes CMH3; the MYH7 second hit changes
    severity, not whether disease occurs. Digenic inheritance in the sense the
    grouping uses requires both loci for the phenotype, which is not what the
    cited South Indian family shows. Recorded here so the call is not
    re-litigated from the paper's title, which does say "digenic".
  evidence:
  - reference: PMID:25607779
    reference_title: "Coexistence of Digenic Mutations in Both Thin (TPM1) and Thick (MYH7) Filaments of Sarcomeric Genes Leads to Severe Hypertrophic Cardiomyopathy in a South Indian FHCM."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thus, we strongly suggest that the coexistence of these digenic mutations
      is rare, but leads to severe hypertrophy in a South Indian familial
      hypertrophic cardiomyopathy (FHCM).
    explanation: >-
      Reports the digenic TPM1-plus-MYH7 genotype and its association with more
      severe hypertrophy.
  - reference: PMID:25607779
    reference_title: "Coexistence of Digenic Mutations in Both Thin (TPM1) and Thick (MYH7) Filaments of Sarcomeric Genes Leads to Severe Hypertrophic Cardiomyopathy in a South Indian FHCM."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient #1 showed a more severe disease phenotype, with poor prognosis and
      a family history of sudden cardiac death, than patient #2.
    explanation: >-
      Within-study contrast between the digenic and the single-TPM1-variant
      proband, supporting the modifier claim.
  - reference: PMID:33642254
    reference_title: "Genotype-phenotype correlations in hypertrophic cardiomyopathy: a multicenter study in Portugal and Spain of the TPM1 p.Arg21Leu variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Six percent of carriers were homozygous and 18% had an additional variant.
    explanation: >-
      Quantifies how often a TPM1 HCM carrier also carries a second variant, the
      population-level basis for treating multi-variant genotype as a modifier.
diagnosis:
- name: Echocardiographic Demonstration of Unexplained Left Ventricular Hypertrophy
  description: >-
    CMH3 is diagnosed, like all HCM, by imaging demonstration of increased left
    ventricular wall thickness that is not explained by abnormal loading
    conditions. Echocardiography defines the distribution of hypertrophy, the
    presence and gradient of dynamic outflow obstruction, and diastolic function;
    hypertrophic pattern differs by causal gene, so echocardiographic morphology
    can inform which gene to prioritise.
  evidence:
  - reference: PMID:38223010
    reference_title: "A Novel TPM1 Mutation Causes Familial Hypertrophic Cardiomyopathy in an Indian Family: Genetic and Clinical Correlation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disorder
      characterised by unexplained left ventricular hypertrophy in the absence of
      abnormal loading conditions.
    explanation: >-
      States the diagnostic criterion applied in a TPM1-variant family report.
  - reference: PMID:37561025
    reference_title: "Gene-echocardiography: refining genotype-phenotype correlations in hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings underscore a strong link between hypertrophic patterns and
      genetic variants in HCM, providing a foundation for more accurate genetic
      testing and personalized management of HCM patients.
    explanation: >-
      Supports using echocardiographic hypertrophy pattern to guide genetic
      testing. PARTIAL because the reported gene-pattern associations concern
      MYBPC3, MYH7, ALPK3, TTN and OBSCN rather than TPM1 specifically.
- name: Sarcomere Gene Panel or Exome Sequencing
  description: >-
    Molecular confirmation requires sequencing of the sarcomere genes; TPM1 is a
    standard panel component. Because TPM1 accounts for only a small share of
    cases, the diagnosis is usually made as part of a multi-gene panel or exome,
    with segregation analysis in relatives to establish causality. Multi-variant
    genotypes are common enough that a TPM1 finding should not stop the search.
  evidence:
  - reference: PMID:38874371
    reference_title: Identification of a novel likely pathogenic TPM1 variant linked to hypertrophic cardiomyopathy in a family with sudden cardiac death.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-exome sequencing (WES) was performed in all available family members
      to identify the causal variant, which was validated, and segregation
      analysis was conducted via Sanger sequencing.
    explanation: >-
      Describes the exome-plus-segregation workflow by which a novel TPM1 CMH3
      allele was established.
  - reference: PMID:33642254
    reference_title: "Genotype-phenotype correlations in hypertrophic cardiomyopathy: a multicenter study in Portugal and Spain of the TPM1 p.Arg21Leu variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TPM1 was evaluated by next-generation sequencing in 10 561 unrelated
      probands with inherited heart diseases.
    explanation: >-
      Documents next-generation sequencing of TPM1 as routine practice in
      inherited-heart-disease diagnostics.
  - reference: PMID:39132495
    reference_title: "ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel: Reappraisal of Genes associated with Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      We report 29 genes with definitive, strong or moderate evidence of
      causation for HCM or isolated LVH, including sarcomere, sarcomere-associated
      and syndromic conditions.
    explanation: >-
      Defines the evidence-backed gene set that an HCM panel should cover, of
      which TPM1 is one. PARTIAL because the quoted conclusion is panel-wide;
      the TPM1-specific Definitive classification is carried by the ClinGen
      CGGV assertion row cited elsewhere in this entry.
- name: Cascade Genetic Testing of At-Risk Relatives
  description: >-
    Once a pathogenic TPM1 variant is identified in a proband, predictive testing
    of first-degree relatives identifies carriers who need longitudinal cardiac
    surveillance and releases non-carriers from it. Because penetrance is
    incomplete and age-dependent - only half of male and a quarter of female
    p.Arg21Leu carriers are diagnosed by age 50 - a normal echocardiogram in a
    young carrier does not exclude later disease.
  evidence:
  - reference: PMID:38874371
    reference_title: Identification of a novel likely pathogenic TPM1 variant linked to hypertrophic cardiomyopathy in a family with sudden cardiac death.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early detection of pathogenic variants can facilitate timely intervention
      and management, potentially reducing the risk of SCD in individuals with
      HCM.
    explanation: >-
      States the rationale for cascade testing in a TPM1 HCM family with sudden
      cardiac death.
  - reference: PMID:33642254
    reference_title: "Genotype-phenotype correlations in hypertrophic cardiomyopathy: a multicenter study in Portugal and Spain of the TPM1 p.Arg21Leu variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At the age of 70 years, 17% of males and 46% of female carriers were
      unaffected.
    explanation: >-
      Quantifies lifelong non-penetrance, the reason cascade-identified carriers
      need continuing rather than one-off surveillance.
  - reference: PMID:32731933
    reference_title: Penetrance of Hypertrophic Cardiomyopathy in Sarcomere Protein Mutation Carriers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Following a first negative screening, approximately 50% of SP mutation
      carriers develop HCM over 15 years of follow-up.
    explanation: >-
      Quantifies conversion after an initially negative screen, the central
      argument for repeat rather than one-off surveillance. PARTIAL because the
      cohort pooled sarcomere-protein genes, of which TPM1 carriers were a small
      minority.
  - reference: PMID:32731933
    reference_title: Penetrance of Hypertrophic Cardiomyopathy in Sarcomere Protein Mutation Carriers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Male sex and an abnormal ECG are associated with a higher risk of
      developing HCM. Regular CMR should be considered in long-term screening.
    explanation: >-
      Identifies the surveillance modifiers (male sex, abnormal ECG) and the
      role of cardiac MRI. The male-sex effect is concordant with the sex
      difference seen in the TPM1 p.Arg21Leu series. PARTIAL for the same
      pooled-gene reason.
- name: Cardiac Magnetic Resonance with Late Gadolinium Enhancement
  diagnosis_term:
    preferred_term: Cardiac magnetic resonance imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  description: >-
    CMR does two things in this genotype that echocardiography does not. It
    measures wall thickness more reliably in the segments where thin-filament
    disease is mildest - the one prospective thin-filament cohort found the
    difference from thick-filament disease significant by both echo and CMR,
    with the CMR comparison the stronger of the two - and late gadolinium
    enhancement quantifies the fibrotic substrate that this entry curates as a
    phenotype and as an arrhythmic mechanism. The second matters
    disproportionately here because the hypertrophy in thin-filament disease is
    milder than in thick-filament disease, so wall thickness alone understates
    disease burden in exactly this population.
  results: >-
    Maximum wall thickness, typically lower than in thick-filament HCM, and late
    gadolinium enhancement marking replacement fibrosis.
  evidence:
  - reference: DOI:10.3390/jcm14030866
    reference_title: "Clinical Features and Prospective Outcomes of Thin-Filament Hypertrophic Cardiomyopathy: Intrinsic Data and Comparative Insights from Other Cohorts"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      individuals with thin-filament mutations exhibited significantly lower
      maximum left ventricular wall thickness, as measured by both
      echocardiography (p = 0.024) and cardiac magnetic resonance (p = 0.006)
    explanation: >-
      Establishes CMR as a measuring modality in this population and the
      thinner-phenotype finding that makes imaging interpretation
      genotype-dependent.
  notes: >-
    The late-gadolinium-enhancement prevalence figure that circulates for
    thin-filament HCM is not quotable from any abstract cached for this entry -
    it comes from the full text of the cohort study. The role of LGE is stated
    here on the strength of the fibrosis phenotype this entry already curates
    rather than on an unverified percentage.
differential_diagnoses:
- name: Thick-Filament Sarcomeric HCM (MYH7, MYBPC3)
  description: >-
    The other, far commoner sarcomeric causes of hypertrophic cardiomyopathy.
    Clinically and histologically overlapping with CMH3 - the histopathology is
    explicitly indistinguishable - so the distinction is molecular. Thick-filament
    disease tends to produce more hypertrophy and more outflow obstruction and
    less restrictive physiology than thin-filament disease.
  distinguishing_features:
  - Distinguished by the causal gene on sequencing, not by histology
  - Greater degrees of LV hypertrophy and outflow obstruction than thin-filament HCM
  - Distinct hypertrophy distributions on echocardiography (mid-septal for MYBPC3, higher septum-to-posterior-wall ratio for MYH7)
  evidence:
  - reference: PMID:9060904
    reference_title: Clinical features of hypertrophic cardiomyopathy caused by mutation of a "hot spot" in the alpha-tropomyosin gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On cardiac histopathologic study, defects in this sarcomere thin filament
      component are indistinguishable from other genetic etiologies of
      hypertrophic cardiomyopathy.
    explanation: >-
      Establishes that histology cannot separate CMH3 from other sarcomeric HCM.
  - reference: PMID:36158814
    reference_title: "Thin filament cardiomyopathies: A review of genetics, disease mechanisms, and emerging therapeutics."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      greater degrees of restrictive cardiomyopathy and relatively less left
      ventricular (LV) hypertrophy and LV outflow tract obstruction than that
      seen with thick filament mutations
    explanation: >-
      Gives the phenotypic tendencies that differentiate thin-filament from
      thick-filament HCM at the group level.
  - reference: PMID:37561025
    reference_title: "Gene-echocardiography: refining genotype-phenotype correlations in hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mid-septal hypertrophy was found to be associated predominantly with myosin
      binding protein C3 (MYBPC3) variants, while a higher septum-to-posterior
      wall ratio correlated with myosin heavy chain 7 (MYH7) variants.
    explanation: >-
      Provides the imaging correlates of the two main thick-filament genes.
- name: TPM1-Related Dilated Cardiomyopathy
  description: >-
    An allelic disorder: different TPM1 substitutions cause dilated rather than
    hypertrophic cardiomyopathy, with a distinct molecular mechanism and a weaker
    (Moderate) ClinGen gene-disease validity classification. A TPM1 variant found
    in a dilated phenotype should not be interpreted using CMH3 evidence.
  disease_term:
    preferred_term: dilated cardiomyopathy
    term:
      id: MONDO:0005021
      label: dilated cardiomyopathy
  distinguishing_features:
  - Chamber dilation with reduced ejection fraction rather than wall thickening
  - Distinct variant set (e.g. E54K, T201M) and distinct molecular mechanism
  - ClinGen gene-disease validity is Moderate, versus Definitive for TPM1-HCM
  evidence:
  - reference: CGGV:assertion_1173d239-23cf-4c9c-9ea5-f95d9356e6c7-2025-04-04T160000.000Z
    reference_title: "TPM1 / dilated cardiomyopathy (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      TPM1 | HGNC:12010 | dilated cardiomyopathy | MONDO:0005021 | AD | Moderate
    explanation: >-
      ClinGen curates TPM1-dilated cardiomyopathy as a separate entity with
      Moderate validity, distinct from the Definitive hypertrophic relationship.
  - reference: PMID:39436707
    reference_title: Distinct mechanisms drive divergent phenotypes in hypertrophic and dilated cardiomyopathy-associated TPM1 variants.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      By contrast, the E54K mutation appeared to act via long-range allosteric
      interactions to increase the association rate of the C-terminal troponin I
      mobile domain to tropomyosin/actin.
    explanation: >-
      Demonstrates a mechanistically distinct lesion for the dilated allele.
- name: TPM1-Related Left Ventricular Noncompaction
  description: >-
    TPM1 variation is also reported in left ventricular noncompaction, a third
    allelic expression with a different imaging phenotype (prominent trabeculation
    with deep intertrabecular recesses).
  phenotypes:
  - name: Left ventricular noncompaction
    phenotype_term:
      preferred_term: Left ventricular noncompaction
      term:
        id: HP:0030682
        label: Left ventricular noncompaction
  distinguishing_features:
  - Prominent LV trabeculation with deep recesses rather than concentric or septal hypertrophy
  evidence:
  - reference: PMID:38223010
    reference_title: "A Novel TPM1 Mutation Causes Familial Hypertrophic Cardiomyopathy in an Indian Family: Genetic and Clinical Correlation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in TPM1 are known to cause hypertrophic cardiomyopathy, dilated
      cardiomyopathy and left ventricular non-compaction.
    explanation: >-
      Names noncompaction as a third TPM1 phenotype requiring differentiation.
progression:
- phase: Preclinical genotype-positive phenotype-negative
  evidence:
  - reference: PMID:33642254
    reference_title: "Genotype-phenotype correlations in hypertrophic cardiomyopathy: a multicenter study in Portugal and Spain of the TPM1 p.Arg21Leu variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TPM1 p.Arg21Leu is a pathogenic HCM variant associated with
      late-onset/incomplete penetrance and a generally favorable prognosis.
    explanation: >-
      Establishes a long genotype-positive, phenotype-negative phase for the
      best-characterized CMH3 allele.
- age_range: Adulthood
  evidence:
  - reference: PMID:33642254
    reference_title: "Genotype-phenotype correlations in hypertrophic cardiomyopathy: a multicenter study in Portugal and Spain of the TPM1 p.Arg21Leu variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The cumulative probability of diagnosis in carriers was 50% at the age of
      50 years for males, and was 25% in female carriers.
    explanation: >-
      Gives the age distribution of clinical onset in TPM1 carriers, with a sex
      effect.
- phase: Paediatric onset
  evidence:
  - reference: PMID:32744700
    reference_title: A novel homozygous TPM1 mutation in familial pediatric hypertrophic cardiomyopathy and in silico screening of potential targeting drugs.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      to our knowledge, this is the first report of the homozygous missense
      variation p.Gly3Arg in TPM1 associated with familial autosomal recessive
      pediatric HCM and PDA.
    explanation: >-
      Documents that biallelic TPM1 genotypes can present in childhood, in
      contrast to the late-onset heterozygous course.
treatments:
- name: Cardiac Myosin Inhibition (Mavacamten)
  description: >-
    Mavacamten is a first-in-class allosteric cardiac myosin inhibitor that
    reduces the number of force-generating crossbridges. It is mechanistically
    well matched to CMH3, whose lesion is failure to keep crossbridges inhibited:
    in patient-derived engineered heart tissue carrying TPM1 E192K, chronic
    mavacamten abolished the contractile difference from control and reversed
    cardiomyocyte hypertrophy. In symptomatic obstructive HCM generally, the
    phase 3 EXPLORER-HCM trial showed improvement in exercise capacity, outflow
    gradient, NYHA class, and health status. The gene-specific evidence is
    preclinical; the clinical trial evidence is genotype-agnostic.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: mavacamten
  target_mechanisms:
  - target: "Cardiomyocyte Hypercontractility and Impaired Relaxation"
    treatment_effect: INHIBITS
    description: >-
      Myosin inhibition reduces the number of force-generating crossbridges,
      directly opposing the hypercontractile node that the TPM1 regulatory defect
      produces.
  target_phenotypes:
  - preferred_term: Left ventricular outflow tract obstruction
    term:
      id: HP:0032092
      label: Left ventricular outflow tract obstruction
  - preferred_term: Exercise intolerance
    term:
      id: HP:0003546
      label: Exercise intolerance
  evidence:
  - reference: PMID:34319370
    reference_title: Loss of crossbridge inhibition drives pathological cardiac hypertrophy in patients harboring the TPM1 E192K mutation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Chronic mavacamten treatment abolished contractile differences between
      control and TPM1 E192K engineered heart tissues and reversed hypertrophy in
      cardiomyocytes.
    explanation: >-
      The gene-specific rationale: myosin inhibition corrects the contractile and
      hypertrophic phenotype of a TPM1 HCM variant in patient-derived tissue.
  - reference: PMID:34319370
    reference_title: Loss of crossbridge inhibition drives pathological cardiac hypertrophy in patients harboring the TPM1 E192K mutation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These studies also provide direct evidence that myosin inhibition by
      mavacamten can counteract the hypertrophic effects of mutant tropomyosin.
    explanation: >-
      Explicitly generalizes the result to mutant tropomyosin, i.e. to CMH3 as a
      class rather than to one allele.
  - reference: PMID:32871100
    reference_title: "Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment with mavacamten improved exercise capacity, LVOT obstruction,
      NYHA functional class, and health status in patients with obstructive
      hypertrophic cardiomyopathy.
    explanation: >-
      Pivotal clinical efficacy evidence. PARTIAL for CMH3 because EXPLORER-HCM
      enrolled symptomatic obstructive HCM without genotype stratification, and
      thin-filament HCM is less often obstructive.
  - reference: PMID:39436707
    reference_title: Distinct mechanisms drive divergent phenotypes in hypertrophic and dilated cardiomyopathy-associated TPM1 variants.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Modulators of myosin activity confirmed our proposed mechanisms by rescuing
      normal contractile behavior in accordance with predictions.
    explanation: >-
      Independent demonstration that myosin modulation rescues the contractile
      abnormality of TPM1 variants, and a caution that the required direction of
      modulation is variant-dependent.
  notes: >-
    The `therapeutic_agent` term binding is intentionally omitted: NCIT does have
    a Mavacamten concept (NCIT:C174901) but it is classified under
    NCIT:C168966 Inotropic Support rather than under NCIT:C1909 Pharmacologic
    Substance, so it is not reachable from the ChemicalEntityTerm roots and fails
    term validation; CHEBI has no mavacamten term. Per the CLAUDE.md convention,
    the agent is carried as free text rather than bound to an unreachable or
    incorrect identifier. This is an upstream NCIT classification gap.

    Direction of therapy is variant-dependent. Myosin inhibition is the correct
    direction for the hypercontractile hypertrophic alleles; the dilated TPM1
    alleles studied alongside them required the opposite modulation, so
    mavacamten should not be extrapolated to a TPM1 carrier with a dilated
    phenotype.
- name: Implantable Cardioverter-Defibrillator for Sudden Death Prevention
  description: >-
    Risk-stratified ICD implantation is the intervention that addresses the
    dominant mortality risk in CMH3. Allele-specific data matter here: calculated
    sudden-death risk was low in 77.5% of p.Arg21Leu carriers, so a TPM1
    diagnosis alone does not justify device therapy, whereas other TPM1 alleles
    have been reported in families ascertained through sudden death.
  action_category: THERAPEUTIC
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
  target_phenotypes:
  - preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: PMID:33642254
    reference_title: "Genotype-phenotype correlations in hypertrophic cardiomyopathy: a multicenter study in Portugal and Spain of the TPM1 p.Arg21Leu variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Calculated HCM sudden death risk was low in 34 carriers (77.5%),
      intermediated in 8 (18%), and high in only 2 (4.5%).
    explanation: >-
      Provides the allele-specific risk distribution that drives the
      device-versus-surveillance decision in the best-characterized CMH3 allele.
  - reference: PMID:38874371
    reference_title: Identification of a novel likely pathogenic TPM1 variant linked to hypertrophic cardiomyopathy in a family with sudden cardiac death.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early detection of pathogenic variants can facilitate timely intervention
      and management, potentially reducing the risk of SCD in individuals with
      HCM.
    explanation: >-
      Supports intervention to reduce sudden-death risk after molecular
      diagnosis. PARTIAL because the paper does not itself evaluate device
      therapy.
- name: Genetic Counseling and Family Screening
  description: >-
    Genetic counseling covers the autosomal dominant 50% recurrence risk,
    age-dependent and sex-modified incomplete penetrance, the possibility of a
    second sarcomere variant in the family, and the implications for reproductive
    and life planning. It is paired with cascade genetic testing and longitudinal
    cardiac surveillance of carriers.
  action_category: COUNSELING_INFORMATIONAL
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:38874371
    reference_title: Identification of a novel likely pathogenic TPM1 variant linked to hypertrophic cardiomyopathy in a family with sudden cardiac death.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The identification of a novel TPM1 variant in a family with HCM and SCD
      underscores the critical role of genetic screening in at-risk families.
    explanation: >-
      Directly supports family genetic screening after a TPM1 CMH3 diagnosis.
  - reference: PMID:33642254
    reference_title: "Genotype-phenotype correlations in hypertrophic cardiomyopathy: a multicenter study in Portugal and Spain of the TPM1 p.Arg21Leu variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At the age of 70 years, 17% of males and 46% of female carriers were
      unaffected.
    explanation: >-
      Supplies the penetrance figures that counseling must convey, including the
      substantial chance of lifelong non-penetrance in female carriers.
experimental_models:
- name: Alpha-TM180 transgenic mouse (TPM1 Glu180Gly)
  description: >-
    Cardiac-restricted transgenic mouse expressing alpha-tropomyosin carrying the
    founding CMH3 allele Glu180Gly. The flagship in vivo model of thin-filament
    HCM and the only model in this entry that reproduces the whole-organ,
    whole-organism course: early concentric hypertrophy with fibrosis and atrial
    enlargement, diastolic dysfunction, increased myofilament calcium
    sensitivity, and death between four and five months.
  experimental_model_type: OTHER
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  publication: PMID:11603924
  modeled_mechanisms:
  - target: "Alpha-Tropomyosin Thin Filament Regulatory Defect"
  - target: "Cardiomyocyte Hypertrophy with Myofiber Disarray and Interstitial Fibrosis"
  - target: "Diastolic Dysfunction and Left Ventricular Outflow Tract Obstruction"
  findings:
  - statement: >-
      Ventricular concentric hypertrophy, fibrosis, and atrial enlargement
      within one month; progressive worsening with death between four and five
      months; diastolic dysfunction and increased myofilament calcium
      sensitivity.
  notes: >-
    Model type is recorded as OTHER because the ExperimentalModelType enum has
    no transgenic-animal value; the organism binding carries the actual model
    identity. This is a transgenic overexpression model, not an endogenous-locus
    knock-in, so it does not reproduce the human 1:1 mutant-to-wild-type
    stoichiometry - see the HUMAN_MODEL_MISMATCH discussion.
  evidence:
  - reference: PMID:11603924
    reference_title: A familial hypertrophic cardiomyopathy alpha-tropomyosin mutation causes severe cardiac hypertrophy and death in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      This study developed transgenic mouse lines that encode an FHC mutation in
      alpha-tropomyosin
    explanation: >-
      Describes construction of the model.
  - reference: PMID:11603924
    reference_title: A familial hypertrophic cardiomyopathy alpha-tropomyosin mutation causes severe cardiac hypertrophy and death in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The disease-associated changes progressively increase and result in death
      between 4 and 5 months.
    explanation: >-
      Gives the model's natural history and endpoint.
- name: Patient-derived engineered heart tissue expressing TPM1 E192K
  description: >-
    Three-dimensional engineered heart tissue generated from cardiomyocytes
    derived from patients carrying TPM1 E192K. Reproduces cellular hypertrophy,
    hypercontractility, and diastolic dysfunction, and was used to demonstrate
    rescue by chronic mavacamten.
  experimental_model_type: IPSC_DERIVED_MODEL
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  publication: PMID:34319370
  modeled_mechanisms:
  - target: "Cardiomyocyte Hypercontractility and Impaired Relaxation"
  findings:
  - statement: >-
      Cellular hypertrophy, hypercontractility, and diastolic dysfunction
      matching the donors' clinical features; contractile differences and
      hypertrophy were abolished by chronic mavacamten.
  evidence:
  - reference: PMID:34319370
    reference_title: Loss of crossbridge inhibition drives pathological cardiac hypertrophy in patients harboring the TPM1 E192K mutation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      To assess the physiological impact of the mutation, we generated
      patient-derived engineered heart tissues expressing E192K.
    explanation: >-
      Describes construction of the model.
- name: Genetically engineered heart tissue expressing TPM1 S215L
  description: >-
    Three-dimensional genetically engineered heart tissue expressing the TPM1
    S215L variant, used together with molecular-dynamics simulation and a Markov
    model of thin-filament activation to reclassify a variant of unknown
    significance as pathogenic.
  experimental_model_type: IPSC_DERIVED_MODEL
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  publication: PMID:36896133
  modeled_mechanisms:
  - target: "Loss of Crossbridge Inhibition and Increased Myofilament Calcium Sensitivity"
  - target: "Cardiomyocyte Hypercontractility and Impaired Relaxation"
  findings:
  - statement: >-
      Hypercontractility, upregulation of hypertrophic gene markers, and
      diastolic dysfunction, supporting reclassification of S215L as
      pathogenic.
  evidence:
  - reference: PMID:36896133
    reference_title: Mechanisms of pathogenicity in the hypertrophic cardiomyopathy-associated TPM1 variant S215L.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Three-dimensional genetically engineered heart tissues expressing TPM1
      S215L exhibited hypercontractility, upregulation of hypertrophic gene
      markers, and diastolic dysfunction.
    explanation: >-
      Describes the model and its phenotype.
- name: Patient hiPSC-derived cardiomyocytes carrying TPM1 Asp175Asn
  description: >-
    Human induced pluripotent stem cell-derived cardiomyocytes from a carrier of
    the founding CMH3 allele Asp175Asn, compared side by side with
    MYBPC3-Gln1061X cardiomyocytes to test whether thin- and thick-filament HCM
    differ at the cellular level.
  experimental_model_type: IPSC_DERIVED_MODEL
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  publication: PMID:27057166
  modeled_mechanisms:
  - target: "Cardiomyocyte Hypercontractility and Impaired Relaxation"
  findings:
  - statement: >-
      Pathological HCM phenotype with cellular enlargement, altered calcium
      handling and electrophysiology, and a gene-expression profile distinct
      from the thick-filament comparator.
  evidence:
  - reference: PMID:27057166
    reference_title: Mutation-Specific Phenotypes in hiPSC-Derived Cardiomyocytes Carrying Either Myosin-Binding Protein C Or alpha-Tropomyosin Mutation for Hypertrophic Cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Both types of HCM-CMs displayed pathological phenotype of HCM but, more
      importantly, we found differences between CMs carrying either
      MYBPC3-Gln1061X or TPM1-Asp175Asn gene mutation in their cellular size,
      Ca(2+) handling, and electrophysiological properties, as well as their gene
      expression profiles.
    explanation: >-
      Describes the model and the mutation-specific result.
discussions:
- discussion_id: tpm1_which_molecular_step_is_rate_limiting
  prompt: >-
    Is the rate-limiting step in CMH3 the mechanical loss of crossbridge
    inhibition, or the increase in myofilament calcium buffering that drives
    calcium-dependent hypertrophic signaling - and does the answer differ by
    allele?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Loss of Crossbridge Inhibition and Increased Myofilament Calcium Sensitivity
  - pathophysiology#Increased Myofilament Calcium Buffering and Calcium-Dependent Signaling
  rationale: >-
    The two hypothesis groups curated here nominate different rate-limiting steps
    and imply different therapeutic targets: myosin inhibition if the mechanical
    arm dominates, calcium-desensitisation if the signaling arm does. The
    supporting studies use different alleles in different systems (S215L, E192K,
    and E62Q in engineered heart tissue; D175N in isolated cardiomyocytes), so no
    single system has tested both arms against each other for the same variant.
    Until that is done the pathograph must carry both arms rather than assert a
    single canonical chain.
  evidence:
  - reference: PMID:29760186
    reference_title: Hypertrophic cardiomyopathy mutations increase myofilament Ca(2+) buffering, alter intracellular Ca(2+) handling, and stimulate Ca(2+)-dependent signaling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Altered myofilament Ca2+ buffering is the primary initiator of signaling
      cascades, indicating that directly targeting myofilament Ca2+ sensitivity
      provides an attractive therapeutic approach in HCM.
    explanation: >-
      One side of the open question, asserting calcium buffering as primary.
  - reference: PMID:36896133
    reference_title: Mechanisms of pathogenicity in the hypertrophic cardiomyopathy-associated TPM1 variant S215L.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These data form a mechanistic description of TPM1 S215L pathogenicity that
      starts with disruption of the mechanical and regulatory properties of
      tropomyosin, leading thereafter to hypercontractility and finally induction
      of a hypertrophic phenotype.
    explanation: >-
      The other side, placing the mechanical/regulatory disruption first in the
      causal order.
- discussion_id: tpm1_allele_to_phenotype_map
  prompt: >-
    What determines whether a given TPM1 substitution produces hypertrophic,
    dilated, restrictive, or noncompaction cardiomyopathy, and can that mapping be
    predicted from the residue's structural role well enough to guide variant
    interpretation?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Divergent Non-Hypertrophic Remodeling Phenotypes
  rationale: >-
    TPM1 is a single small gene with at least four distinct cardiomyopathy
    outputs, and within a single family the same variant can produce diastolic
    dysfunction in one relative and overt HCM in another, while compound
    heterozygosity produced restrictive disease in a child. One paired study
    offers a molecular explanation for the hypertrophic-versus-dilated split, but
    it covers two variants. Without a systematic allele-to-mechanism-to-phenotype
    map, a novel TPM1 missense finding cannot be assigned to CMH3 rather than to
    its allelic siblings on mechanistic grounds, and the therapeutic direction
    (myosin inhibition versus activation) is not determinable from the genotype.
  evidence:
  - reference: PMID:32882290
    reference_title: The effect of tropomyosin variants on cardiomyocyte function and structure that underlie different clinical cardiomyopathy phenotypes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a large family with DCM carrying a recently identified TPM1
      gene variant (T201M) and a child with RCM with compound heterozygote TPM1
      variants (E62Q and M281T) whose family members carrying single variants
      show diastolic dysfunction and HCM.
    explanation: >-
      Illustrates the within-gene and within-family phenotypic divergence that
      the gap concerns.
  - reference: PMID:32217077
    reference_title: "Mutation-specific pathology and treatment of hypertrophic cardiomyopathy in patients, mouse models and human engineered heart tissue."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Several mutation-mediated disease mechanisms have been identified, with
      proof for gene- and mutation-specific cellular perturbations.
    explanation: >-
      Confirms that mutation-specific mechanism is an established phenomenon in
      HCM, making an allele-resolved map a realistic rather than speculative goal.
- discussion_id: tpm1_hcm_human_model_fidelity
  prompt: >-
    Do engineered heart tissues and hiPSC-cardiomyocytes carrying TPM1 variants
    faithfully model adult human CMH3, given that they are immature, lack the
    fibrotic and neurohormonal context, and in several studies overexpress the
    variant rather than carry it at endogenous dose?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Cardiomyocyte Hypercontractility and Impaired Relaxation
  rationale: >-
    Almost all of the mechanistic evidence for CMH3 curated here comes from
    engineered tissue, hiPSC-cardiomyocytes, reconstituted filaments, or
    simulation - the human clinical literature supplies genotype-phenotype
    correlation but essentially no mechanism. These systems reproduce
    hypercontractility and diastolic dysfunction convincingly, but they cannot
    reproduce the fibrosis, disarray, and neurohormonal remodeling that dominate
    the clinical disease, and overexpression studies replaced a substantial
    fraction of endogenous protein. The direction of a reported effect can even
    invert between systems: one variant panel reported reduced calcium-transient
    amplitude in overexpressing cardiomyocytes, whereas the buffering study
    reported increased diastolic calcium. This is an open question of
    translational validity rather than an absence of evidence.
  evidence:
  - reference: PMID:32882290
    reference_title: The effect of tropomyosin variants on cardiomyocyte function and structure that underlie different clinical cardiomyopathy phenotypes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      To define toxic threshold levels, we performed dose-dependent transfection
      of TPM1 variants.
    explanation: >-
      Documents that the model relies on transfected overexpression at
      experimenter-set dose, the specific fidelity concern raised here.
  - reference: PMID:32217077
    reference_title: "Mutation-specific pathology and treatment of hypertrophic cardiomyopathy in patients, mouse models and human engineered heart tissue."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The pros and cons of these experimental models for studying
      mutation-specific HCM pathology and therapies will be outlined.
    explanation: >-
      A dedicated review of exactly this model-fidelity question for HCM,
      confirming it is a recognized open issue rather than a curation artefact.
  - reference: PMID:10900175
    reference_title: Effect of hypertrophic cardiomyopathy mutations in human cardiac muscle alpha-tropomyosin (Asp175Asn and Glu180Gly) on the regulatory properties of human cardiac troponin determined by in vitro motility assay.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The results using human cardiac regulatory proteins reveal different
      effects of the HCM mutations in tropomyosin compared to studies using
      heterologous systems.
    explanation: >-
      The sharpest statement of the fidelity problem for this specific gene:
      for TPM1, non-human or heterologous systems give qualitatively different
      answers, so a mechanistic result is only as trustworthy as its protein
      isoform context.
  - reference: PMID:10900175
    reference_title: Effect of hypertrophic cardiomyopathy mutations in human cardiac muscle alpha-tropomyosin (Asp175Asn and Glu180Gly) on the regulatory properties of human cardiac troponin determined by in vitro motility assay.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      There is growing evidence that the precise isoforms of both the mutated
      protein and its interacting partners can qualitatively influence the
      effects of the mutation.
    explanation: >-
      States the general principle underlying the mismatch: for thin-filament
      mutations the interacting-partner isoform set can invert the direction of
      a measured effect.
  - reference: PMID:11603924
    reference_title: A familial hypertrophic cardiomyopathy alpha-tropomyosin mutation causes severe cardiac hypertrophy and death in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Expression of exogenous mutant tropomyosin leads to a concomitant decrease
      in endogenous alpha-tropomyosin without altering the expression of other
      contractile proteins.
    explanation: >-
      The transgenic model works by displacing endogenous tropomyosin rather
      than reproducing the human 1:1 mutant-to-wild-type allelic stoichiometry -
      the same overexpression caveat raised for the cellular models, and
      pointed at the very stoichiometry hypothesis proposed in the founding
      CMH3 paper.
- discussion_id: tpm1_arrhythmic_risk_and_risk_scd_calibration
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What is the true arrhythmic risk in TPM1 hypertrophic cardiomyopathy, and do
    the established HCM sudden-death risk models calibrate correctly in
    thin-filament disease?
  attaches_to:
  - phenotypes#Sudden Cardiac Death
  - phenotypes#Non-Sustained Ventricular Tachycardia
  rationale: >-
    The literature points in two directions at once, and the disagreement is not
    resolvable from the published evidence. Narrative reviews of thin-filament
    cardiomyopathy describe a high sudden-death risk marked by family history,
    non-sustained ventricular arrhythmia and abnormal exercise blood-pressure
    response. The one prospective thin-filament cohort with nearly five years of
    follow-up reports the opposite: no malignant arrhythmic event occurred in any
    thin-filament patient, and its authors state directly that the higher-risk
    claim is controversial between studies and depends on age of onset and
    genotype within individual families. Both readings cannot be right for the
    same population.
    The practical consequence is a calibration question rather than an academic
    one. The conventional sudden-death risk models were derived on cohorts
    dominated by thick-filament genotypes, and the same cohort study found
    thin-filament patients had milder hypertrophy - the dominant input to those
    models - while progressing to advanced heart failure roughly five times
    faster. A model driven by wall thickness may therefore systematically
    under-call risk in a genotype whose danger is weighted toward heart failure
    rather than toward hypertrophy, or may correctly identify a genuinely lower
    arrhythmic risk. Nothing in the current evidence distinguishes those.
    TPM1 specifically cannot settle it: it accounted for 9 of 285 carriers in the
    largest penetrance cohort and a minority of the 15 thin-filament patients in
    the outcome cohort.
  evidence:
  - reference: DOI:10.3390/jcm14030866
    reference_title: "Clinical Features and Prospective Outcomes of Thin-Filament Hypertrophic Cardiomyopathy: Intrinsic Data and Comparative Insights from Other Cohorts"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      None of the thin-filament HCM patients experienced malignant arrhythmic
      events.
    explanation: >-
      The prospective observation that contradicts the high-arrhythmic-risk
      framing, in the only thin-filament cohort with follow-up.
  - reference: DOI:10.3390/jcm14030866
    reference_title: "Clinical Features and Prospective Outcomes of Thin-Filament Hypertrophic Cardiomyopathy: Intrinsic Data and Comparative Insights from Other Cohorts"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Data on a higher risk of malignant arrhythmias in thin-filament HCM remain
      controversial between studies and rather depend on the age of onset and
      genotype in each particular family.
    explanation: >-
      The authors state the controversy explicitly, which is what makes this a
      knowledge gap rather than a settled contradiction to be resolved in favour
      of one side.
  - reference: DOI:10.3390/jcm14030866
    reference_title: "Clinical Features and Prospective Outcomes of Thin-Filament Hypertrophic Cardiomyopathy: Intrinsic Data and Comparative Insights from Other Cohorts"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      showed more rapid progression to advanced heart failure (HR = 5.6, p =
      0.018)
    explanation: >-
      The quantified heart-failure hazard that makes the risk profile in this
      class weighted toward heart failure rather than arrhythmia, which is the
      substance of the calibration concern.
  proposed_experiments:
  - experiment_id: tpm1_thin_filament_risk_scd_calibration
    name: External validation of HCM sudden-death risk models in thin-filament genotypes
    description: >-
      Pool thin-filament HCM patients across the existing genotyped registries
      and assess calibration of the established risk models - observed versus
      predicted event rates, stratified by thin-filament versus thick-filament
      genotype. The cohorts required already exist and are genotyped; what is
      missing is the stratified calibration analysis. A systematic
      under-prediction in thin-filament carriers would justify a genotype term in
      risk assessment, and a correct calibration would settle the controversy in
      the other direction.
references:
- reference: PMID:20301725
  title: Nonsyndromic Hypertrophic Cardiomyopathy Overview.
  tags:
  - GeneReviews
- reference: PMID:36158814
  title: "Thin filament cardiomyopathies: A review of genetics, disease mechanisms, and emerging therapeutics."
- reference: PMID:32217077
  title: "Mutation-specific pathology and treatment of hypertrophic cardiomyopathy in patients, mouse models and human engineered heart tissue."
notes: >-
  Scope. This entry models MONDO:0007267 (hypertrophic cardiomyopathy 3), the
  TPM1 node of the CMH numbered series, and conforms to the
  cardiomyopathy_maladaptive_remodeling module at its trigger, ventricular
  remodeling, contractile dysfunction, and heart failure nodes. It is
  deliberately kept as a gene-specific entity under the umbrella
  `Hypertrophic_Cardiomyopathy` (MONDO:0005045) entry rather than folded into it:
  the umbrella carries the population epidemiology, the physiological
  obstructive/non-obstructive subtypes, and the full generic HCM treatment set
  (beta blockers, calcium channel blockers, septal myectomy, alcohol septal
  ablation), none of which is duplicated here. ICD is the one exception and is
  curated here rather than delegated, because risk stratification in
  thin-filament disease is genotype-dependent in a way the generic set is not -
  see the arrhythmic-risk knowledge gap, which records that the two available
  bodies of evidence disagree about whether this class carries elevated or
  reduced arrhythmic risk. What this entry adds is the
  TPM1-specific causal chain, the thin-filament-versus-thick-filament phenotype
  contrast, the allele-resolved genotype-phenotype and prognosis data, and the
  gene-specific mavacamten rationale.

  Named Entity Confusion preflight (per CLAUDE.md). The CMH numbered series is a
  documented high-NEC-risk class, so MONDO:0007267 was verified with OAK before
  any curation: the definition names TPM1 as the causal gene, the record carries
  `relationship: RO:0004003 HGNC:12010 ! TPM1`, the OMIM xref is OMIM:115196, and
  synonyms include CMH3 and "cardiomyopathy, familial hypertrophic, 3". Every
  gene-level claim in this entry concerns TPM1. The MONDO parent is
  MONDO:0024573 (familial hypertrophic cardiomyopathy).

  Deep-research provenance. The requested provider was Edison/FutureHouse
  (falcon), but no EDISON_API_KEY or FUTUREHOUSE_API_KEY was available in the
  curation environment and the provider registry reported only `claude_code` as
  available, so the `claude_code` provider was used instead. Regardless of
  provider, the report was NEC-preflighted before use (TPM1 named 125 times
  versus 19 for the next-most-frequent gene MYBPC3, and OMIM 115196 asserted
  throughout, both matching the MONDO record) and then treated as leads only: every PMID cited
  here was fetched with `just fetch-reference`, every snippet was verified as an
  exact substring of the cached abstract by `just validate-references`, and every
  ontology term was checked by `just validate-terms`.

  Evidence balance and its limits. The human literature on CMH3 is
  genotype-phenotype correlation, not mechanism; the mechanism comes almost
  entirely from reconstituted filaments, molecular dynamics, hiPSC-cardiomyocytes,
  engineered heart tissue, and one transgenic mouse line (the Glu180Gly
  alpha-TM180 model, PMID:11603924, which supplies the only whole-organism
  evidence in this entry). Evidence items are typed accordingly
  (COMPUTATIONAL for simulation-derived claims, IN_VITRO for filament assays and
  engineered tissue, HUMAN_CLINICAL for pedigree and cohort data), and the
  resulting translational-validity question is recorded explicitly as a
  HUMAN_MODEL_MISMATCH discussion rather than glossed. Several mechanistic
  studies characterize alleles (E192K, D219V, S215L) whose independent clinical
  pathogenicity rests on small numbers of families; the explanations name the
  allele in each case so the reader can see which variant a given claim rests on.

  GeneReviews scope. There is no TPM1-specific GeneReviews chapter. The
  applicable resource is the disease-level "Nonsyndromic Hypertrophic
  Cardiomyopathy Overview" (PMID:20301725), tagged accordingly in `references`.
  Its indexed PubMed record contains only the chapter's six-clause purpose
  statement, not the Clinical Characteristics or Management sections, so
  section-by-section GeneReviews mining is not possible from the cache and no
  snippet is quoted from it. The clinical-characteristics baseline for this entry
  is therefore built from the primary TPM1 cohort and pedigree literature
  (PMID:9060904, PMID:33642254, PMID:38874371, PMID:38223010) plus the
  thin-filament cardiomyopathy review (PMID:36158814).

  Frequency discipline. Frequency bands are given only where a source supports
  them. Left ventricular hypertrophy is VERY_FREQUENT and hypertrophic
  cardiomyopathy itself OBLIGATE (it is the defining feature of the entity);
  outflow obstruction and heart failure are OCCASIONAL as a qualitative mapping
  of the thin-filament class comparison, and those items are marked PARTIAL
  because no TPM1-specific rate is published. Most other phenotypes carry no
  frequency band rather than a guessed one.

  Content deliberately not curated, recorded so it is not repeatedly re-raised.
  Several figures that circulate for thin-filament and TPM1 hypertrophic
  cardiomyopathy are not quotable from any source cached for this entry, and are
  omitted rather than attached to a citation that does not contain them: the
  cohort percentages for non-sustained ventricular tachycardia, symptomatic
  dyspnea and late gadolinium enhancement all come from the full text and tables
  of the thin-filament outcome study rather than its abstract, which is what is
  cached; the case-control odds ratio showing no HCM excess for truncating TPM1
  variants comes from a web-hosted variant atlas rather than from a paper with a
  quotable abstract; and the Finnish p.Asp175Asn founder-population detail is
  likewise not present in any cached record. The underlying claims are
  plausible and in several cases important - the truncating-variant negative in
  particular is the observation that grounds a gain-of-function rather than
  haploinsufficiency mechanism - but this entry states them only where a cached
  source supports them. The truncating-variant point is instead made
  qualitatively where the evidence does support it: every curated TPM1 allele in
  this entry is missense.
📚

References & Deep Research

References

3
PMID:20301725
Nonsyndromic Hypertrophic Cardiomyopathy Overview.
No top-level findings curated for this source.
PMID:36158814
Thin filament cardiomyopathies: A review of genetics, disease mechanisms, and emerging therapeutics.
No top-level findings curated for this source.
PMID:32217077
Mutation-specific pathology and treatment of hypertrophic cardiomyopathy in patients, mouse models and human engineered heart tissue.
No top-level findings curated for this source.

Deep Research

1
Claude Code ▸
1. Disease Information
claude-haiku-4-5-20251001, claude-opus-5[1m] 53 citations 2026-08-01T21:17:38.021073

1. Disease Information

Overview

Hypertrophic cardiomyopathy 3 (CMH3) is the TPM1-related molecular subtype of familial hypertrophic cardiomyopathy — an autosomal dominant sarcomeric (thin-filament) cardiomyopathy defined by increased left ventricular wall thickness in the absence of an abnormal loading condition, with the histologic triad of cardiomyocyte hypertrophy, myocyte/myofibrillar disarray, and replacement/interstitial fibrosis. It is one of the nine "definitive" monogenic sarcomere-gene HCM entities and one of the two original thin-filament HCM genes described in the landmark sarcomere paper of Thierfelder et al.

Thierfelder L, Watkins H, MacRae C, Lamas R, McKenna W, Vosberg HP, Seidman JG, Seidman CE. Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere. Cell. 1994 Jun 3;77(5):701–12. PMID:8205619

Key conclusion (paraphrased from abstract): missense substitutions Asp175Asn and Glu180Gly in the α-tropomyosin gene cause FHC linked to chromosome 15q2; because α-tropomyosin, cardiac troponin T, and β-myosin heavy chain mutations produce the same disease, "FHC is a disease of the sarcomere." The authors further propose that "abnormal stoichiometry of sarcomeric proteins can cause cardiac hypertrophy."

Two features distinguish CMH3 from thick-filament (MYH7/MYBPC3) HCM in the classical literature: (i) hypertrophy is often milder / less impressive relative to the clinical risk, and (ii) at least for some variants the arrhythmic/heart-failure burden is disproportionate to wall thickness. Watkins H, et al. Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy. N Engl J Med. 1995;332(16):1058–64. PMID:7898523 — α-tropomyosin mutations account for ~3% of FHC, and these mutations are "characterized by relatively mild and sometimes subclinical hypertrophy but a high incidence of sudden death."

Key identifiers

Resource Identifier
MONDO MONDO:0007267 — hypertrophic cardiomyopathy 3 (OAK-verified)
OMIM (phenotype) 115196 — CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 3; CMH3
OMIM (gene) 191010 — TROPOMYOSIN 1; TPM1
MedGen CUI C1861863, UID 349382
UMLS C1861863
Disease Ontology DOID:0110309
MeSH C566170
GARD GARD:0024541
HGNC hgnc:12010 (TPM1) — note dismech lowercase convention
UniProt P09493 (Tropomyosin alpha-1 chain)
Cytoband 15q22.2
MONDO subsets rare, nord_rare, gard_rare

MONDO definition (OAK, verbatim): "Any hypertrophic cardiomyopathy in which the cause of the disease is a mutation in the TPM1 gene." Parent: MONDO:0024573 familial hypertrophic cardiomyopathy. Logical definition: MONDO:0005045 and RO:0004003 some HGNC:12010.

Synonyms (from MONDO/MedGen — all OAK-verified)

  • CMH3
  • TPM1 hypertrophic cardiomyopathy
  • cardiomyopathy, familial hypertrophic, 3 / type 3
  • cardiomyopathy, hypertrophic, 3
  • hypertrophic cardiomyopathy type 3
  • hypertrophic cardiomyopathy caused by mutation in TPM1
  • TPM1-Related Familial Hypertrophic Cardiomyopathy (MedGen)
  • α-tropomyosin–related HCM (literature usage)

Data provenance character

CMH3 knowledge is overwhelmingly aggregated disease-level and family-based, not EHR-derived: OMIM/MONDO gene-series curation, ClinGen gene-disease validity curation, kindred-based genotype–phenotype series (Finnish D175N founder cohorts; the Iberian R21L cohort), sarcomere-gene registry cohorts (SHaRe-type, Italian/Russian centers), plus a large in-vitro/biophysical and transgenic-animal mechanistic literature. Population-scale variant frequency comes from gnomAD/ExAC case–control burden analyses. There is no dedicated CMH3 EHR phenotype or registry; individual-level data come from clinical genetics cohorts.

2. Etiology

2.1 Primary causal factor

Heterozygous (monoallelic) missense variants in TPM1, encoding α-tropomyosin — the ~284-residue, α-helical coiled-coil dimer that lies in the actin filament groove and, together with the troponin complex, gates myosin access to actin in a Ca²⁺-dependent, three-state (blocked → closed → open) manner. Mechanism of disease at the gene level per ClinGen: altered gene product sequence, autosomal dominant, monoallelic; reported pathogenic variant class is missense.

Critically for variant interpretation: truncating TPM1 variants are not an HCM mechanism. In the largest published case–control burden analysis (4,447 HCM cases vs ExAC; Atlas of Cardiac Genetic Variation / cardiodb ACGV):

Variant class Case freq. Reference freq. Excess Odds ratio (95% CI)
All rare protein-altering 1.484% 0.086% 1.40% (p<0.0001) 17.33 (11.83–25.51)
Non-truncating — — 1.40% (p<0.0001) 18.04 (12.26–26.68)
Truncating — — 0.00% (p=1.0) 0.00 (0.00–25.38)

Etiological fraction 0.94 (0.92–0.96) — i.e. ~94% of HCM patients carrying a rare TPM1 variant are likely to have disease caused by it. Source: cardiodb ACGV TPM1/HCM page (derived from Walsh R, et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med 2017 — [PMID UNVERIFIED: commonly cited as 27532257]).

2.2 Genetic risk factors

Causal variants (see §4 for full detail). The two archetypes are p.Asp175Asn and p.Glu180Gly (Thierfelder 1994, PMID:8205619). Residue 175/180 sits in a troponin-T–binding region of the tropomyosin molecule — this is the reason the substitutions are cardiac-specific and functionally potent (stated in the α-TM180 transgenic mouse literature, PMID:11603924).

Recurrent mutation / hot spot. Coviello DA, et al. Clinical features of hypertrophic cardiomyopathy caused by mutation of a "hot spot" in the alpha-tropomyosin gene. J Am Coll Cardiol. 1997;29(3):635–40 [PMID UNVERIFIED] — three kindreds with independently arising Asp175Asn; the authors propose that nucleotide 579 (G→A transition, exon 5) has increased susceptibility to mutation.

De novo mutation is documented. Watkins H, et al. A de novo mutation in alpha-tropomyosin that causes hypertrophic cardiomyopathy. Circulation. 1995. PMID:7729014 — so a negative family history does not exclude CMH3.

Modifier / background genetic risk. Common-variant polygenic background substantially modifies both penetrance and expressivity in sarcomere-variant carriers: Harper AR, Goel A, Grace C, et al. Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity. Nat Genet. 2021 Feb;53(2):135–142. DOI 10.1038/s41588-020-00764-0. [PMID UNVERIFIED — commonly cited as 33495597] — GWAS of 2,780 cases / 47,486 controls identified 12 genome-wide-significant HCM susceptibility loci; a genetic risk score halved HCM odds in the lowest quintile and doubled them in the highest, and influenced phenotypic severity in sarcomere-variant carriers.

Sex as a genetic-background modifier. Male sex is an independent predictor of conversion from genotype-positive/phenotype-negative to overt HCM: HR 2.91 (Lorenzini M, et al. Penetrance of Hypertrophic Cardiomyopathy in Sarcomere Protein Mutation Carriers. JACC. 2020;76(5):550–559. PMID:32731933). Concordantly, in the Iberian TPM1 p.Arg21Leu cohort, cumulative diagnosis probability at age 50 was 50% in male vs 25% in female carriers (PMID:33642254).

2.3 Environmental risk factors

CMH3 is monogenic; environment acts as a modifier of expressivity and of arrhythmic/ischemic triggering, not as a cause:

  • Elevated diastolic blood pressure — Mendelian randomization in Harper et al. 2021 identified DBP as a key modifiable risk factor (a 1-SD DBP increase raised HCM risk ~4-fold in sarcomere-negative HCM). Afterload is therefore plausibly a modifier of hypertrophic expressivity in variant carriers, though this was derived in sarcomere-negative disease.
  • Intense/competitive exercise — the classical trigger context for SCD in HCM; HCM is the most commonly reported cause of SCD in US athletes (~36% in some series) and >80% of affected individuals are asymptomatic before SCD.
  • Acidosis / ischemia as a decompensating exposure — mechanistically supported specifically for tropomyosin FHC mutations: "Functional effects of a tropomyosin mutation linked to FHC contribute to maladaptation during acidosis" (PMC3035739).
  • Age — penetrance is strongly age-dependent (§9).
  • Family history — the dominant risk factor in practice; drives cascade screening.

No toxin, infectious, occupational, or radiation exposure is implicated in CMH3 causation. Not applicable / no evidence found: dietary, pollutant, or occupational etiologic factors.

2.4 Protective factors

  • Genetic: low-percentile HCM polygenic score is associated with roughly halved odds of HCM expression (Harper 2021) — the closest thing to a documented protective genetic factor. No specific protective TPM1 allele or modifier allele has been reported.
  • Environmental/therapeutic: blood-pressure control (from the DBP MR result) and, at the level of secondary prevention, cardiac myosin inhibition and ICD therapy (§12). Historically, restriction from high-intensity competitive sport was considered protective; the 2024 AHA/ACC guideline substantially liberalized exercise recommendations (§12–13).
  • Not available: no dietary, supplement, or gnomAD-derived protective-variant data specific to TPM1.

2.5 Gene–environment interactions

Documented interactions are (i) genotype × sex (male carriers convert to overt HCM ~3× more often; PMID:32731933, PMID:33642254); (ii) rare variant × polygenic background (Harper 2021); (iii) rare variant × afterload/DBP (Harper 2021, MR); (iv) mutant tropomyosin × intracellular acidosis — a true molecular GxE, where the mutant thin filament responds maladaptively to acidotic pH (PMC3035739, in vitro/model organism). No CTD-registered chemical–gene interaction relevant to CMH3 was identified.

3. Phenotypes

CMH3 phenotype is the HCM phenotype with a thin-filament flavor: comparable or lesser wall thickness for a given clinical burden, high late-gadolinium-enhancement (fibrosis) prevalence, and faster progression to advanced heart failure. Frequencies below are drawn from thin-filament HCM cohorts (where TPM1 is the largest constituent gene) and from TPM1-specific kindreds; frequencies are cohort-specific and should be curated conservatively — per the dismech frequency-evidence SOP, omit frequency: where the snippet supports only the association.

3.1 Core structural phenotypes

Phenotype HPO term (OAK-verified) Onset Severity/course Frequency & evidence
Hypertrophic cardiomyopathy HP:0001639 Hypertrophic cardiomyopathy Adolescent–adult (variable) Progressive Obligate/defining
Left ventricular hypertrophy HP:0001712 Left ventricular hypertrophy Adult typical Progressive Defining; max wall thickness 17 mm median in thin-filament vs 21 mm thick-filament (p=0.024) — Chumakova OS, et al. J Clin Med. 2025;14(3):866
Asymmetric septal hypertrophy HP:0001670 Asymmetric septal hypertrophy Adult Variable TPM1 characteristically anterior/septal; D175N kindreds: mean max wall thickness 24±4.5 mm anterior septum (family DT), 15±2.7 mm (family DB), 18±2.1 mm posterior septum (family MI) — Coviello 1997 [PMID UNVERIFIED]
Left ventricular outflow tract obstruction HP:0032092 Left ventricular outflow tract obstruction Adult Variable 33% of thin-filament cohort (Chumakova 2025)
Myocardial fibrosis HP:0001685 Myocardial fibrosis Adult Progressive LGE present in 88% of thin-filament patients (Chumakova 2025); replacement fibrosis on histology in D175N (Coviello 1997)
LV diastolic dysfunction HP:0025168 Left ventricular diastolic dysfunction Early, often pre-hypertrophic Progressive Central to mechanism; documented in α-TM180 mouse (PMID:11603924) and in S215L engineered tissue (20% slower relaxation; PMID:36896133)
Mitral regurgitation HP:0001653 Mitral regurgitation Adult Variable Secondary to SAM/LVOTO in obstructive disease

3.2 Arrhythmic and sudden-death phenotypes

Phenotype HPO term Notes
Sudden cardiac death HP:0001645 Sudden cardiac death α-tropomyosin mutations described with "relatively mild and sometimes subclinical hypertrophy but a high incidence of sudden death" (PMID:7898523). A novel TPM1 missense variant produced a malignant young-onset pedigree: 12 affected members, 5 died young, others only mildly affected — "malignant phenotype at young age with a variable clinical manifestation and penetrance at older age" (PMID:12651045)
Ventricular tachycardia (NSVT) HP:0004756 Ventricular tachycardia 13% NSVT in the thin-filament cohort (Chumakova 2025); other cohorts report higher NSVT incidence in thin-filament/TPM1 HCM — literature is genuinely discordant
Atrial fibrillation HP:0005110 Atrial fibrillation Standard HCM complication; atrial enlargement is an early feature of the α-TM180 mouse
Arrhythmia (general) HP:0011675 Arrhythmia —
Cardiac arrest HP:0001695 Cardiac arrest —
Abnormal EKG HP:0003115 Abnormal EKG Abnormal ECG is the strongest predictor of phenotype conversion, HR 4.02 (PMID:32731933) — and frequently precedes hypertrophy

3.3 Symptomatic phenotypes

Phenotype HPO term Onset/course Notes
Dyspnea HP:0002094 Dyspnea Adult, progressive 53% of thin-filament patients symptomatic at diagnosis (Chumakova 2025)
Chest pain HP:0100749 Chest pain Episodic Angina from microvascular ischemia/demand mismatch
Syncope HP:0001279 Syncope Episodic Major SCD risk marker
Palpitations HP:0001962 Palpitations Episodic —
Exercise intolerance HP:0003546 Exercise intolerance Progressive Peak VO₂ is the SEQUOIA-HCM primary endpoint domain
Congestive heart failure HP:0001635 Congestive heart failure Late 20% of thin-filament patients progressed to advanced HF vs 7% thick-filament; mean survival free of advanced HF 5.2 ± 0.64 y vs 11.8 ± 1.04 y, HR 5.6, p=0.018 (Chumakova 2025)

3.4 Cellular/histopathologic phenotypes (for category: Cellular and histopathology)

  • Cardiomyocyte hypertrophy — >3-fold increased cardiomyocyte volume in TPM1 S215L hiPSC-CM/engineered tissue (PMID:36896133); >3-fold peak force increase for E62Q (PMID:39436707).
  • Myocyte and myofibrillar disarray — in the OMIM/MedGen definition itself: CMH3 is "an autosomal dominant disorder characterized by increased myocardial mass with myocyte and myofibrillar disarray" (MedGen C1861863, verbatim).
  • Replacement and interstitial fibrosis — Coviello 1997; α-TM180 mouse (PMID:11603924).
  • Hypertrophic gene program activation — upregulation of MYH7, NPPB (BNP), NPPA (ANP), GATA4, FHL1 in S215L engineered heart tissue (PMID:36896133, IN_VITRO).

3.5 Quality-of-life impact

No CMH3-specific PRO study exists. Generalizable HCM data: aficamten produced "substantial improvements across a broad range of clinically relevant efficacy measures" including symptoms and health status (KCCQ) in SEQUOIA-HCM (NCT05186818), and EXPLORER-HCM (NCT03470545) met its primary and all secondary endpoints (p≤0.0006), which included KCCQ-CSS and NYHA class. Per-phenotype QoL attribution for CMH3 specifically is not available; the dominant QoL determinants in HCM are exertional dyspnea, exercise limitation, arrhythmia/ICD-related anxiety, and — for genotype-positive relatives — surveillance burden.

4. Genetic / Molecular Information

4.1 Causal gene

TPM1 — tropomyosin 1 (alpha), hgnc:12010, OMIM 191010, chromosome 15q22.2, UniProt P09493. The cardiac/striated-muscle isoform is transcript NM_001018005.2 (MANE Select for variant nomenclature in ClinVar). Protein: 284-residue α-helical coiled-coil homodimer* with a 7-fold quasi-repeat ("periods") of actin-binding sites; polymerizes head-to-tail into a continuous strand along both grooves of the actin filament; binds actin, troponin T, and (indirectly) troponin I. GO annotations of relevance: GO:0051015 actin filament binding, GO:0031014 troponin T binding, GO:0005884 actin filament, GO:0030017 sarcomere, GO:0030016 myofibril (all OAK-verified).

ClinGen gene–disease validity: DEFINITIVE for HCM. Hespe S, Waddell A, Asatryan B, et al. ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel: Reappraisal of Genes associated with Hypertrophic Cardiomyopathy. PMID:39132495 (medRxiv 2024; JACC 2025, doi 10.1016/j.jacc.2024.12.010). TPM1 retained its Definitive classification from the 2019 curation; Table 2 records autosomal dominant inheritance, monoallelic autosomal requirement, altered-gene-product-sequence mechanism, and missense as the reported pathogenic variant class. In the same reappraisal, 31 genes were re-curated + 5 new candidates; 17/31 (55%) changed classification (1 limited, 4 disputed from no-known-relationship, 9 disputed from limited, 3 definitive from moderate), and TNNC1 was upgraded as a 9th definitive sarcomere gene. Panel: 29 individuals, 21 institutions, 6 countries.

4.2 Pathogenic variants

Variant (protein) cDNA (NM_001018005.2) rsID ClinVar germline Phenotype notes Key PMIDs
p.Asp175Asn (D175N) c.523G>A rs104894503 Pathogenic, 2★ ("criteria provided, multiple submitters, no conflicts"), 6 submissions, last eval. 2025-12-02; GRCh38 chr15:63060899 Archetype; Finnish founder; mild–moderate HCM, favorable prognosis, high adult penetrance; recurrent (hot spot at nt 579) 8205619, 22462493, 15000344, Coviello 1997
p.Glu180Gly (E180G) c.539A>G rs104894502 Pathogenic, 0★ (no assertion criteria), 2 submissions, last eval. 1994-06-03; GRCh38 chr15:63060915 Archetype; largest Ca²⁺-sensitization of the pair; basis of the severe α-TM180 mouse 8205619, 11603924
p.Val95Ala (V95A) — — Reported pathogenic "Mild cardiac phenotype, abnormal calcium binding to troponin, abnormal myosin cycling, and poor prognosis" Karibe A, et al. Circulation. 2001;103(1):65 [PMID UNVERIFIED]
p.Arg21Leu (R21L) — — Pathogenic Iberian founder (Galicia, Extremadura, N. Portugal); 25/4,099 (0.61%) HCM probands, absent in 6,462 non-HCM inherited-cardiac controls (p<0.0001); 83 carriers/31 probands; late-onset, incomplete penetrance, generally favorable prognosis 33642254
p.Ser215Leu (S215L) — — VUS→pathogenic by functional modeling Full mechanistic pipeline: destabilized blocked state, +1.0 pCa₅₀ unit Ca²⁺ sensitization 36896133
p.Glu62Gln (E62Q) — — HCM-associated >3-fold ↑ peak force (hypercontractile); rescued by mavacamten 39436707
Novel missense (malignant pedigree) — — Pathogenic 12 affected, 5 young deaths; malignant young-onset with variable later penetrance 12651045
De novo variant — — Pathogenic Establishes de novo occurrence 7729014

Allele frequency. ClinVar records D175N at "extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: <0.001%)" (verbatim). E180G has no gnomAD frequency in its ClinVar record. Aggregate reference-population frequency for all rare protein-altering TPM1 variants was 0.086% in ExAC vs 1.484% in 4,447 HCM cases (cardiodb ACGV).

Variant type/class. Exclusively missense (altered gene product sequence) for the HCM phenotype. Truncating variants confer no HCM excess (OR 0.00) — this is an important negative and should be curated explicitly: a TPM1 truncating variant found in an HCM patient is not evidence for CMH3.

Origin. Germline, autosomal dominant, mostly inherited, with documented de novo occurrence (PMID:7729014). Somatic TPM1 variation is not a CMH3 mechanism. No COSMIC/TCGA relevance.

Functional consequence class. Not loss of function and not haploinsufficiency — a dominant, poison-peptide/altered-function mechanism operating on the thin filament: the mutant α-tropomyosin incorporates into the filament and changes its mechanical stiffness and its regulatory-state equilibria (see §6). The most precise statement available for the HCM direction of effect is increased thin-filament activation / hypercontractility with impaired relaxation — arguably a gain of function at the level of filament activation, achieved by loss of the inhibitory (blocked-state) function of tropomyosin.

4.3 Allelic disorders (same gene, different disease — keep as separate dismech entries)

TPM1 is a pleiotropic cardiac gene. These are not CMH3 and should be modeled as distinct entities:

  • Dilated cardiomyopathy 1Y (CMD1Y) — e.g. p.Glu54Lys (E54K): ~3-fold decrease in peak force, 42% faster time-to-peak, 50% faster relaxation (PMID:39436707).
  • Left ventricular noncompaction 9 (LVNC9) — e.g. p.Lys30Glu (K30E), pediatric LVNC + DCM via impaired structural/functional properties of cardiac tropomyosin (PMC11641563).
  • Restrictive cardiomyopathy — p.Glu181Lys (E181K, c.541G>A), sporadic pediatric RCM, proposed to act by suppressing CaMKII/HDAC4 signaling (Fu J, Zhang J, et al., Frontiers in Genetics; PMC12818787). Note this residue is immediately adjacent to the classical E180G HCM residue — a striking example of position-adjacent phenotypic divergence.
  • Congenital heart defects/septal defects have been reported for TPM1 in some panels; evidence is weaker and should not be asserted without primary verification.

Suggested Discussion / mechanistic_hypotheses framing: the HCM-vs-DCM-vs-RCM divergence within TPM1 is the flagship unresolved question for this gene, and is now partially explained (§6.6).

4.4 Modifier genes

  • Polygenic HCM background (12 GWAS loci; PRS quintile effect) — Harper 2021, Nat Genet 53:135–142.
  • Sex (male, HR 2.91) and abnormal ECG (HR 4.02) as clinical/biological modifiers of penetrance — PMID:32731933.
  • Compound/multi-variant sarcomere genotypes are a recognized severity modifier in HCM generally; specific TPM1 digenic reports were not identified in this search. No named single-gene modifier locus is established for CMH3.

4.5 Epigenetics

No CMH3-specific methylation or histone-modification dataset was identified. The only chromatin-adjacent mechanistic thread is the CaMKII → HDAC4 axis implicated for the TPM1 E181K restrictive phenotype (PMC12818787) — HDAC4 nuclear export is the canonical link from Ca²⁺/CaMKII signaling to MEF2-dependent hypertrophic transcription, so this is a plausible (but for CMH3 unproven) route from altered myofilament Ca²⁺ handling to a transcriptional hypertrophy program. Flag as a knowledge gap. ENCODE/Roadmap/DiseaseMeth: nothing CMH3-specific.

4.6 Chromosomal abnormalities

Not applicable. CMH3 is caused by single-nucleotide missense substitutions. No aneuploidy, translocation, inversion, or recurrent CNV mechanism; chromosomal microarray has no diagnostic role (§10).

5. Environmental Information

  • Environmental factors: none causal. No CTD/TOXNET chemical–disease association for CMH3. Elevated diastolic blood pressure is the best-supported modifiable factor in the broader HCM genetics literature (Harper 2021, Mendelian randomization).
  • Lifestyle factors: high-intensity/competitive athletics as an SCD trigger context (HCM = leading cause of SCD in US athletes in historical series; most HCM deaths nonetheless occur at rest); systemic hypertension and obesity as afterload/expressivity modifiers; alcohol as an AF trigger. Note: dehydration/vasodilators/large meals precipitate LVOT obstruction symptoms in obstructive HCM — a pharmacologic/behavioral, not etiologic, exposure.
  • Infectious agents: not applicable — no pathogen is implicated in CMH3.

6. Mechanism / Pathophysiology

6.1 Causal chain (proposed dismech pathograph)

[MOLECULAR]  TPM1 missense variant (e.g. D175N, E180G, S215L, E62Q)
 ↓  incorporation of mutant α-tropomyosin into the cardiac thin filament
[MOLECULAR]  Altered tropomyosin mechanics + regulatory-state equilibria
     (↓ coiled-coil stiffness / ↑ flexibility; destabilized blocked state;
      azimuthal shift toward closed/open positions on actin)
 ↓
[MOLECULAR]  Increased Ca²⁺ sensitivity of thin-filament activation
     + residual cross-bridge activity at diastolic [Ca²⁺]
 ↓
[CELLULAR]   Cardiomyocyte hypercontractility + impaired/incomplete relaxation
     (diastolic dysfunction) + inefficient ATP utilization / energetic cost
 ↓
[CELLULAR]   Hypertrophic signaling activation (Ca²⁺/CaMKII → HDAC4/MEF2 proposed;
     GATA4, MYH7, NPPA, NPPB, FHL1 upregulation) → cardiomyocyte hypertrophy
 ↓
[TISSUE]     Myocyte + myofibrillar disarray; interstitial and replacement fibrosis;
     microvascular remodeling/ischemia; atrial enlargement
 ↓
[TISSUE]     Asymmetric LV/septal hypertrophy; LVOT obstruction (± SAM, mitral regurg.);
     arrhythmogenic substrate (dispersion of repolarization, reentry around fibrosis)
 ↓
[ORGANISM]   Diastolic heart failure / advanced HF; ventricular tachyarrhythmia;
     atrial fibrillation; syncope; sudden cardiac death

Upstream = the tropomyosin mechanical/regulatory defect (molecular). Downstream = hypertrophy, fibrosis, arrhythmic substrate, heart failure (tissue/organism). The energetic-inefficiency and impaired-relaxation nodes are the ones on which the therapeutic myosin inhibitors act.

6.2 Molecular pathway detail — thin filament regulation

The three-state (blocked–closed–open) steric-blocking model is the pathway. HCM TPM1 variants shift the equilibrium away from "blocked":

Bing W, et al. Effect of hypertrophic cardiomyopathy mutations in human cardiac muscle alpha-tropomyosin (Asp175Asn and Glu180Gly) on the regulatory properties of human cardiac troponin determined by in vitro motility assay. J Mol Cell Cardiol. 2000 Aug. PMID:10900175. Abstract, verbatim excerpt:

"The expected switching off of reconstituted filament movement at pCa9, and switching on at pCa5, was observed with no difference in fraction of filaments motile or filament velocity, between wild-type and mutant filaments. However, we observed increased Ca(2+) sensitivity of fraction of filaments motile using the mutant tropomyosin compared to wild-type (DeltaEC(50) +0.082+/-0.019 pCa units for Asp175Asn and +0.115+/-0.021 for Glu180Gly). Indirect measurements using immobilized alpha-actinin to retard filament movement showed that filaments reconstituted with mutant AStm produced the same force as wild-type filaments."

Note the nuance for careful curation: in this human-protein reconstituted system the mutants sensitize Ca²⁺ activation but produce the same force — i.e. Ca²⁺ sensitization, not raw force gain, is the primary in-vitro signature, and E180G > D175N.

Supporting structural/biophysical evidence (all IN_VITRO / COMPUTATIONAL): - PMID:21376702 — D175N and E180G "shift tropomyosin strands further towards the open position during the ATPase cycle." - PMID:22794249 — long-range effects of E180G and D175N on tropomyosin properties; changed affinity for actin, effect of E180G > D175N. - PMID:9109674 — Golitsina et al., effects of the two mutations on α-tropomyosin structure and function. - PMID:15454401 — altered thermal unfolding of actin-bound tropomyosin. - Loong et al., FEBS Lett. 2012 — E180G "markedly reduces persistence length, implying increased flexibility"; F-actin affinity of E180G similar to wild type. - Halder et al. (below) — quantified stiffness loss: 21% measured / 57% predicted reduction in tropomyosin stiffness for E62Q; 54% reduction for S215L.

6.3 Integrated mechanism — S215L pipeline (the best-documented full chain)

Halder SS, Rynkiewicz MJ, Creso JG, et al. Mechanisms of pathogenicity in the hypertrophic cardiomyopathy-associated TPM1 variant S215L. PNAS Nexus. 2023 Jan;2(1):pgad011. PMID:36896133. Abstract, verbatim excerpt:

"These data form a mechanistic description of TPM1 S215L pathogenicity that starts with disruption of the mechanical and regulatory properties of tropomyosin, leading thereafter to hypercontractility and finally induction of a hypertrophic phenotype."

Findings: destabilization of the blocked regulatory state with increased tropomyosin chain flexibility; ~1.0 pCa₅₀ unit increase in Ca²⁺ sensitivity; MD-derived 54% reduction in tropomyosin stiffness; Markov modeling predicting hypercontractile twitches and prolonged relaxation; engineered heart tissue showing 3-fold increased isometric contraction, 20% slower relaxation, greater diastolic stiffness, >3-fold increased cardiomyocyte volume, and upregulation of MYH7, BNP, ANP, GATA4, FHL1; and a greater relative drop in diastolic stress after acute mavacamten in S215L, indicating elevated residual cross-bridge activity in diastole.

6.4 The force-homeostasis framework (HCM vs DCM within TPM1)

Halder SS, Rynkiewicz MJ, Kim L, Barry ME, Zied AGA, Sewanan LR, Kirk JA, Moore JR, Lehman WJ, Campbell SG. Distinct mechanisms drive divergent phenotypes in hypertrophic and dilated cardiomyopathy–associated TPM1 variants. J Clin Invest. 2024 Dec 16;134(24):e179135. PMID:39436707. Abstract, verbatim excerpt:

"Heritable forms of hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) represent starkly diverging clinical phenotypes, yet may be caused by mutations to the same sarcomeric protein. The precise mechanisms by which point mutations within the same gene bring about phenotypic diversity remain unclear. Our objective was to develop a mechanistic explanation of diverging phenotypes in two TPM1 mutations, E62Q (HCM) and E54K (DCM)."

Results: E62Q — >3-fold increase in peak force, 21% decreased tropomyosin stiffness (57% predicted), increased blocked→closed equilibrium constant favoring the closed state and preventing effective myosin inhibition. E54K — ~3-fold decrease in peak force, 42% faster time-to-peak, 50% faster relaxation, driven by long-range allosteric increase in the association rate of the troponin-I mobile domain to tropomyosin/actin, reducing myosin recruitment. The two residues are only 8 amino acids apart on the same actin-binding repeat. The unifying claim: mutations that elevate baseline contractility drive hypertrophy (HCM); those that reduce it drive elongation without hypertrophy (DCM) — a contractile-force-homeostasis / mechanosensing framework. Myosin modulators reversed both directions (mavacamten for E62Q, danicamtiv for E54K), which the authors take as confirmation that the framework transcends the specific molecular lesion.

This is the single most useful citation for a dismech mechanistic_hypotheses block on CMH3.

6.5 Cellular processes and downstream tissue mechanisms

  • Impaired relaxation / incomplete diastolic deactivation → elevated diastolic stress, subendocardial and microvascular ischemia.
  • Energetic inefficiency — excess tension cost per ATP; the classical "energy compromise" hypothesis for sarcomeric HCM. Direct TPM1 ATPase-cycle evidence: PMID:21376702.
  • Ca²⁺ handling remodeling — differential between variants in vivo: in transgenic rats, "Ca²⁺ sensitivity of cardiac skinned-fiber preparations from animals with mutation Asp175Asn, but not Glu180Gly, was decreased," and "elevated frequency and amplitude of spontaneous Ca²⁺ waves were detected only in cardiomyocytes from animals with mutation Asp175Asn" (AJP Regul Integr Comp Physiol 2004, doi 10.1152/ajpregu.00620.2003) — i.e. an arrhythmogenic Ca²⁺-wave phenotype specifically in D175N.
  • Tropomyosin phosphorylation as a modifiable node — "Decreasing Tropomyosin Phosphorylation Rescues Tropomyosin-induced Familial Hypertrophic Cardiomyopathy" (PMC3789987) — a druggable-node hypothesis worth recording.
  • Fibrosis — interstitial and replacement fibrosis; in dismech terms, CMH3 is a candidate conformer to fibrotic_response at the myocardial-fibrosis node, and to cardiomyopathy_maladaptive_remodeling (see §Curation notes).
  • Immune system involvement — not applicable; no autoimmune or immunodeficiency component. Sterile inflammatory amplification of fibrosis is plausible but not documented specifically for CMH3.
  • Metabolic changes — increased tension cost/ATP consumption and impaired energetics (inferred from the sarcomeric-HCM literature); no TPM1-specific metabolomic dataset. HMDB/Metabolomics Workbench: nothing CMH3-specific.

6.6 Suggested ontology terms for mechanism (all OAK-verified)

GO biological process / molecular function: | Term | ID | Use | |---|---|---| | regulation of cardiac muscle contraction | GO:0055117 | core dysregulated process | | regulation of cardiac muscle contraction by calcium ion signaling | GO:0010882 | Ca²⁺-sensitization node | | regulation of muscle filament sliding | GO:0032971 | thin-filament gating | | muscle filament sliding | GO:0030049 | cross-bridge cycling | | regulation of actin filament-based movement | GO:1903115 | in-vitro motility readout | | actin filament binding | GO:0051015 | α-tropomyosin MF | | troponin T binding | GO:0031014 | residue 175/180 interaction region | | cardiac muscle hypertrophy | GO:0003300 | downstream hypertrophy | | positive regulation of cardiac muscle hypertrophy | GO:0010613 | signaling arm | | sarcomere organization | GO:0045214 | disarray | | ATP hydrolysis activity | GO:0016887 | energetics | | regulation of calcium ion transport into cytosol | GO:0010522 | Ca²⁺-wave arm (D175N rat) |

GO cellular component: GO:0030017 sarcomere, GO:0030016 myofibril, GO:0005884 actin filament, GO:0005861 troponin complex, GO:1990584 cardiac Troponin complex.

CL cell types: CL:0000746 cardiac muscle cell; CL:2000046 ventricular cardiac muscle cell (preferred for CMH3). Note CL:0008023 cardiac fibroblast is obsolete — do not use; use a valid fibroblast term or omit.

CHEBI: CHEBI:29108 calcium(2+); CHEBI:15422 ATP.

6.7 Molecular profiling and advanced technologies

  • Transcriptomics: hypertrophic marker induction (MYH7, NPPA, NPPB, GATA4, FHL1) in TPM1 S215L engineered heart tissue (PMID:36896133). No published bulk or single-cell RNA-seq dataset of human CMH3 myocardium was identified. GEO/GTEx: nothing CMH3-specific.
  • Proteomics / metabolomics / lipidomics: no CMH3-specific dataset identified. PRIDE/MetaboLights/LIPID MAPS: nothing found.
  • Single-cell and spatial transcriptomics: not available for CMH3 specifically (general HCM myocardium snRNA-seq atlases exist but are not TPM1-stratified).
  • Structural/computational: molecular dynamics of the actin–tropomyosin–troponin complex is the workhorse for CMH3 (PMID:36896133, PMID:39436707); Markov-model myofilament simulation ("Predicting Effects of Tropomyosin Mutations on Cardiac Muscle Contraction through Myofilament Modeling," Front Physiol 2016). AlphaFold/PDB: coiled-coil tropomyosin and cryo-EM thin-filament structures underpin the stiffness calculations.
  • Functional genomics screens (CRISPR/RNAi): no TPM1-HCM screen identified; DepMap is not informative for this indication. CRISPR is used for isogenic hiPSC-CM model construction, not screening.
  • hiPSC-CM / engineered tissue: the dominant modern platform. Patient-derived hiPSC-CMs carrying TPM1-D175N (Finnish founder) show "pathological phenotypes of HCM with differences in cellular size, Ca²⁺ handling, and electrophysiological properties" compared with MYBPC3-mutant lines (Ojala M, et al., PMC4707351). 3D genetically engineered heart tissues expressing TPM1 variants show "hypercontractility, upregulation of hypertrophic gene markers, and diastolic dysfunction."

7. Anatomical Structures Affected

Organ level

  • Primary organ: heart — UBERON:0000948 (OAK-verified). Body system: cardiovascular.
  • Primary sub-structures: UBERON:0002084 heart left ventricle; UBERON:0002094 interventricular septum (the characteristic TPM1 anterior/septal distribution; UBERON:0004667 interventricular septum muscular part for finer granularity); UBERON:0002349 myocardium.
  • Secondary involvement: left atrium (atrial enlargement, AF — atrial enlargement is an early feature in the α-TM180 mouse, within 1 month); mitral valve apparatus (SAM, mitral regurgitation); lungs (pulmonary congestion in diastolic HF); systemic circulation and brain (cardioembolic stroke from AF). Coronary microvasculature (microvascular remodeling/ischemia).

Tissue and cell level

  • Tissue: cardiac muscle tissue (striated muscle); cardiac interstitium/connective tissue (fibrosis).
  • Cells: CL:0000746 cardiac muscle cell / CL:2000046 ventricular cardiac muscle cell (primary); cardiac fibroblasts (secondary, fibrotic arm — note the specific CL term is obsolete); endothelial cells of coronary microvasculature (secondary).

Subcellular level

  • GO:0030017 sarcomere — the primary compartment; specifically the thin (actin) filament (GO:0005884 actin filament) and the troponin–tropomyosin regulatory unit (GO:0005861 troponin complex, GO:1990584 cardiac Troponin complex).
  • GO:0030016 myofibril — the disorganized structure in myofibrillar disarray.
  • Sarcoplasmic reticulum / cytosolic Ca²⁺ compartment implicated secondarily (Ca²⁺-wave phenotype in D175N rats).

Localization / lateralization

  • Bilateral in the sense of being a systemic genetic disease of the myocardium, but structurally asymmetric: septal-predominant, typically anterior septum, with a characteristically asymmetric hypertrophy pattern (HP:0001670). Left-ventricular predominant; right ventricular involvement uncommon. Apical and concentric variants occur.

8. Temporal Development

Onset

  • Typical onset: adolescent to adult. Mean age at diagnosis in a thin-filament HCM cohort (60% TPM1) was 44 years (Chumakova 2025). Iberian R21L: cumulative diagnosis probability 50% by age 50 (males).
  • Pediatric/childhood onset occurs and can be lethal — a novel TPM1 missense pedigree with 12 affected members and 5 young deaths, described as a "malignant phenotype at young age" (PMID:12651045). Congenital onset is not typical for CMH3 (contrast the TPM1 LVNC/RCM allelic phenotypes, which are pediatric).
  • Onset pattern: insidious and chronic. Very often the first detectable abnormality is an abnormal ECG preceding hypertrophy — abnormal ECG was the strongest predictor of subsequent HCM development in mutation carriers (HR 4.02, PMID:32731933).
  • Suggested OnsetDescriptor: onset_category: ADULT_ONSET at the entity level, with a documented pediatric/juvenile tail.

Progression

  • Course: chronic, lifelong, progressive, punctuated by episodic arrhythmic events. Never self-limited; spontaneous remission does not occur.
  • Stages: (i) genotype-positive/phenotype-negative (G+/P−) — the surveillance stage, with subtle ECG/tissue-Doppler/CMR abnormalities; (ii) overt nonobstructive or obstructive HCM with preserved EF; (iii) adverse remodeling with progressive fibrosis, AF, and functional decline; (iv) end-stage/"burnt-out" HCM with systolic dysfunction (LVEF <50%) or restrictive physiology requiring advanced therapy/transplant.
  • Progression rate — thin-filament disease progresses faster to advanced HF. Chumakova OS, Baklanova TN, Zateyshchikov DA. Clinical Features and Prospective Outcomes of Thin-Filament Hypertrophic Cardiomyopathy. J Clin Med. 2025;14(3):866, doi 10.3390/jcm14030866. Abstract, verbatim: "In adults, thin-filament HCM is associated with a 'thinner' phenotype and a more rapid progression to advanced heart failure compared to thick-filament HCM. Data on a higher risk of malignant arrhythmias in thin-filament HCM remain controversial between studies." Mean survival free of advanced HF: "5.2 ± 0.64 years in the thin-filament group compared to 11.8 ± 1.04 years" (thick-filament), HR 5.6, p=0.018; advanced HF 20% vs 7%.
  • Variant-dependent trajectory. Finnish D175N is described as mild-to-moderate HCM with favorable prognosis and high adult penetrance (91–95%); the three D175N kindreds of Coviello 1997 had markedly different wall thickness but "survival was comparable and favorable." Conversely V95A was reported with a mild phenotype but poor prognosis (Karibe 2001), and some novel variants produce malignant young-onset disease (PMID:12651045). CMH3 is repeatedly singled out as "one of the clearest extreme examples of intra- and interfamilial variability among subjects carrying the same variant."

Patterns

  • Remission: none spontaneous. Treatment-induced symptomatic remission is achievable — LVOT gradient normalization and functional-class improvement with cardiac myosin inhibitors, myectomy, or alcohol septal ablation. This is symptom/hemodynamic remission, not disease reversal.
  • Critical periods / intervention windows: (i) adolescence through the fourth–fifth decade — the highest-yield surveillance interval, when most conversion occurs; (ii) the G+/P− window, the target of prevention-of-phenotype trials; (iii) the peri-competitive-athletics period for SCD risk; (iv) pre-advanced-HF, before irreversible fibrosis accumulates (88% LGE prevalence in thin-filament disease argues this window is often already partly lost at diagnosis); (v) pregnancy and peripartum, requiring specialized management.

9. Inheritance and Population

Epidemiology

  • HCM overall: clinically detected prevalence ≈ 1 in 500 (0.2%); genotypic/subclinical prevalence estimated as high as ~1 in 200. HCM prevalence in highly trained athletes has been directly studied (PMID:18325444).
  • CMH3 share of HCM: ~1–5%, with important cohort dependence:
  • ~3% of FHC classically (PMID:7898523).
  • 3.2% of sarcomere-positive carriers: in 285 individuals from 156 families, gene distribution was MYBPC3 43.2%, MYH7 24.2%, TNNI3 13.7%, TNNT2 11.9%, TPM1 3.2%, MYL2 2.1%, ACTC1 0.4% (PMID:32731933).
  • 1.484% of 4,447 HCM probands carried a rare protein-altering TPM1 variant (cardiodb ACGV), of which ~94% are causal (etiological fraction 0.94) → ~1.4% attributable fraction.
  • Some contemporary series report <1%.
  • Finland: 6.5–11% (founder effect, below).
  • Derived CMH3 prevalence estimate: ~1/500 × ~2% ≈ ~4 per 100,000 (prevalence_class: BAND_1_9_PER_100000), rising to perhaps ~20/100,000 in Finland. This is a derivation, not a published figure — curate as notes with the two source numbers, or use prevalence_class alone. Orphanet does not publish a CMH3-specific prevalence.
  • Incidence: no CMH3-specific incidence figure available. HCM SCD incidence estimates range 0.5–13 per 100,000 in US data.

Inheritance

  • Pattern: Autosomal dominant (HP:0000006), monoallelic, with documented de novo occurrence (PMID:7729014). ClinGen records "monoallelic autosomal" as the genetic mechanism.
  • Penetrance: incomplete and age-dependent. Lorenzini M, et al. JACC. 2020;76(5):550–559. PMID:32731933 — 285 G+/P− carriers from 156 families, median age 14.2 y, 49.5% male; "Estimated HCM penetrance at 15 years of follow-up was 46% (95% CI: 38% to 54%)"; 86 (30.2%) developed HCM over median 8.0 y follow-up; independent predictors male sex (HR 2.91) and abnormal ECG (HR 4.02). Gene-specific 15-year penetrance: TPM1 42% (vs MYH7 66%, TNNT2 50%, MYBPC3 43%, TNNI3 17%).
  • Variant-specific penetrance differs sharply: Finnish D175N shows high adult penetrance (91–95%), whereas Iberian R21L shows late-onset, incomplete penetrance — at age 70, 17% of male and 46% of female carriers remained unaffected (PMID:33642254).
  • Expressivity: highly variable, both between and within families carrying the same variant — Coviello 1997 documented mean maximal wall thickness ranging 15±2.7 to 24±4.5 mm across three D175N kindreds; TPM1 is cited as among the most extreme examples of intra/interfamilial variability in HCM.
  • Genetic anticipation: not applicable — no repeat expansion mechanism; no anticipation reported.
  • Germline mosaicism: not reported for TPM1; de novo variants are documented (PMID:7729014), so mosaicism cannot be excluded but is not established. Knowledge gap.
  • Founder effects — two well-documented:
  • Finland, TPM1-D175N. Jääskeläinen P, et al. Two founder mutations in the alpha-tropomyosin and the cardiac myosin-binding protein C genes are common causes of hypertrophic cardiomyopathy in the Finnish population. Ann Med. 2013. PMID:22462493. Abstract, verbatim excerpts: "We screened for two founder mutations (TPM1-D175N and MYBPC3-Q1061X) in 306 unrelated Finnish patients with HCM from the regions covering a population of ∼4,000,000." … "The TPM1-D175N mutation was found in 20 patients (6.5%) and the MYBPC3-Q1061X in 35 patients (11.4%). Altogether, the two mutations accounted for 17.9% of the HCM cases. In addition, 61 and 59 relatives of the probands were found to be carriers of TPM1-D175N and MYBPC3-Q1061X, respectively. The mutations showed regional clustering. TPM1-D175N was prevalent in central and western Finland, and MYBPC3-Q1061X in central and eastern Finland." In eastern Finland specifically, D175N accounted for ~11% of cases with haplotype evidence of a founder event (Jääskeläinen P, et al. Genetics of hypertrophic cardiomyopathy in eastern Finland: few founder mutations with benign or intermediary phenotypes. PMID:15000344). TPM1 is the most prevalent thin-filament HCM gene in Finland (6–11%).
  • Iberia, TPM1-p.Arg21Leu. PMID:33642254 — 25/4,099 (0.61%) HCM probands from 10,561 screened inherited-cardiac-disease probands; absent in 6,462 non-HCM controls (p<0.0001); 83 carriers in 31 pedigrees concentrated in Galicia, Extremadura, and northern Portugal, indicating a founder effect; pathogenic, late-onset/incomplete penetrance, generally favorable prognosis.
  • Additional recurrent-mutation caveat: the D175N G→A transition at nt 579 arose independently in multiple kindreds (Coviello 1997), so recurrence ≠ founder in every case.
  • Consanguinity: no role — autosomal dominant, monoallelic disease.
  • Carrier frequency: the concept does not apply as in recessive disease. The relevant population figure is the rare TPM1 variant frequency in reference populations: 0.086% (ExAC), with D175N at gnomAD v4.1 total AF <0.001%. In Finland, D175N carrier frequency is elevated relative to global (founder effect); a specific Finnish gnomAD figure was not retrieved.

Population demographics

  • Higher-prevalence populations: Finns (D175N, especially central/western Finland; 6.5% nationally, ~11% eastern Finland). Galicians, Extremadurans, and northern Portuguese (R21L). South African subpopulations have documented HCM founder profiles though not TPM1-specific in the retrieved source.
  • Geographic distribution of variants: as above — D175N is pan-population but enriched in Finland; E180G is sporadic/global; R21L is Iberian; S215L, E62Q from North American/European cohorts; novel variants reported from India (PMC10784234) and Russia.
  • Sex ratio: TPM1 variants are transmitted 1:1, but clinical expression is male-predominant. Male sex HR 2.91 for phenotype conversion (PMID:32731933); R21L cumulative diagnosis by age 50 was 50% male vs 25% female (PMID:33642254). Ascertained clinical CMH3 cohorts should therefore be expected male-skewed; the underlying carrier sex ratio is 1:1.
  • Age distribution: carriers span all ages; diagnosis clusters in the 4th–6th decades (mean 44 y in thin-filament cohort), with a clinically important pediatric/young-adult tail carrying disproportionate SCD risk.

10. Diagnostics

Diagnosis of CMH3 = clinical/imaging diagnosis of HCM + molecular confirmation of a pathogenic TPM1 variant. The governing document is the 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy, Circulation/JACC 2024, PMID:38718139.

Clinical / imaging tests

Test Role Terms
Transthoracic echocardiography (± provocation/Valsalva, exercise stress echo) First-line diagnosis: maximal wall thickness ≥15 mm (≥13 mm with family history), asymmetric septal hypertrophy, LVOT gradient, SAM, diastolic indices, LA size NCIT:C16525 Echocardiography Test (OAK-verified)
Cardiac MRI with late gadolinium enhancement Wall-thickness accuracy, apical/atypical variants, fibrosis quantification (LGE in 88% of thin-filament HCM — a key CMH3-relevant number), SCD risk refinement, phenocopy discrimination NCIT cardiac-MRI term needs OAK lookup; RadLex applicable
12-lead ECG Often the earliest abnormality, preceding hypertrophy; HR 4.02 for subsequent HCM in carriers (PMID:32731933) HP:0003115 Abnormal EKG
Ambulatory ECG (24–48 h / extended) NSVT detection for SCD risk stratification (13% NSVT in thin-filament cohort) HP:0004756
Exercise testing / CPET (peak VO₂) Functional assessment; the SEQUOIA-HCM efficacy domain; exercise-induced hypotension as risk marker —
Cardiac biomarkers (NT-proBNP, hs-troponin) Prognostic/monitoring; NT-proBNP is a mavacamten dose-titration and monitoring input LOINC applicable
Endomyocardial biopsy / explant histopathology Not routine diagnostically; establishes the myocyte hypertrophy + disarray + replacement fibrosis triad (Coviello 1997) —
Electrophysiology study Selected cases; the D175N literature includes a study relating inducibility of life-threatening ventricular arrhythmias to maximum LV thickness and clinical SCD markers in D175N carriers (J Mol Cell Cardiol / Elsevier, S0022282803003237) —

Genetic testing

  • Recommended approach: multigene cardiomyopathy/HCM panel covering at minimum the definitive sarcomere genes (MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC1, TNNC1) plus phenocopy genes (PRKAG2, GLA, LAMP2, TTR, DES, FHL1, ALPK3, FLNC, CSRP3, ACTN2, FHOD3, JPH2, TRIM63), performed in the proband with pre-/post-test genetic counseling; followed by targeted cascade (site-specific) testing of at-risk relatives. This is a Class 1 pathway in the 2024 guideline (PMID:38718139) and the GTR/GeneReviews standard.
  • Single-gene TPM1 testing: appropriate only for cascade testing of a known familial variant, or in a founder population where a specific variant is being screened — the Finnish authors explicitly conclude: "The TPM1-D175N and MYBPC3-Q1061X mutations account for a substantial part of all HCM cases in the Finnish population, indicating that routine genetic screening of these mutations is warranted in Finnish patients with HCM" (PMID:22462493, verbatim).
  • WES/WGS: reserved for panel-negative cases, syndromic presentations, or research; no established incremental yield for isolated HCM over a curated panel.
  • Variant interpretation caveats specific to TPM1: (i) only missense variants are interpretable as HCM-causing — truncating variants show zero case excess (OR 0.00) and should not be reported as HCM-causal; (ii) ClinGen classifies TPM1–HCM as Definitive, so PP4/PS4-type evidence is usable; (iii) reference-population frequency for rare TPM1 variants is only 0.086%, so BS1/BA1 thresholds are stringent; (iv) functional-modeling pipelines have been used to reclassify TPM1 VUS (S215L, PMID:36896133) — an emerging PS3 evidence route.
  • Not applicable to CMH3: chromosomal microarray, karyotyping, FISH, mitochondrial DNA testing, repeat-expansion testing. Each may be relevant in the differential (e.g. mtDNA testing for mitochondrial cardiomyopathy phenocopies, CMA for syndromic hypertrophy in infants) but not for CMH3 itself.

Omics-based diagnostics

  • RNA-seq: research use for splice-variant resolution; no established CMH3 diagnostic role.
  • Proteomics / metabolomics / epigenomics / liquid biopsy: not applicable / not available for CMH3 diagnosis.

Clinical criteria and differential diagnosis

  • Criteria: 2024 AHA/ACC HCM guideline (PMID:38718139) — LV wall thickness ≥15 mm (≥13 mm in relatives of affected individuals or genotype-positive individuals) not explained by abnormal loading conditions.
  • Differential diagnosis:
  • Physiologic: athlete's heart; hypertensive LVH; aortic stenosis–related hypertrophy; obesity-related remodeling.
  • Other genetic HCM: MYBPC3, MYH7, TNNT2, TNNI3, TNNC1, MYL2, MYL3, ACTC1, ALPK3, FHOD3, CSRP3, ACTN2 — distinguished only by genotype.
  • Phenocopies (critical to exclude, different treatment): Fabry disease (GLA), Danon disease (LAMP2), PRKAG2 glycogen-storage cardiomyopathy, ATTR cardiac amyloidosis, Noonan/RASopathy cardiomyopathy, mitochondrial cardiomyopathy, Pompe disease (infantile), Friedreich ataxia cardiomyopathy.
  • Other TPM1 allelic entities: CMD1Y (dilated), LVNC9, TPM1 restrictive cardiomyopathy — same gene, different phenotype; do not merge with CMH3.

Screening

  • Cascade genetic screening of first-degree relatives after proband variant identification — the cornerstone (Class 1).
  • Serial clinical surveillance of genotype-positive/phenotype-negative relatives — ECG + echocardiography, typically every 1–2 years in children/adolescents and every 3–5 years in adults, informed by the 46% 15-year penetrance and the ECG-precedes-hypertrophy pattern (PMID:32731933).
  • Population/newborn screening: not indicated and not performed.
  • Founder-variant population screening is a defensible targeted strategy in Finland (PMID:22462493).

11. Outcome / Prognosis

Survival and mortality

  • No CMH3-specific survival curve exists. In the thin-filament cohort (60% TPM1), all-cause mortality was 0 and stroke 0 over 4.7 years' follow-up, with no significant mortality difference vs thick-filament HCM (Chumakova 2025) — a small cohort (n=15) whose zero-event arms should be read as low short-term event rates, not as absence of risk.
  • Counterbalancing this, the historical α-tropomyosin literature emphasizes "relatively mild and sometimes subclinical hypertrophy but a high incidence of sudden death" (PMID:7898523), and specific pedigrees have been catastrophic (12 affected, 5 young deaths; PMID:12651045). Prognosis in CMH3 is variant-specific, not gene-specific — the single most important curation caveat for this entry.
  • Variant-level prognosis: D175N — favorable ("survival was comparable and favorable," Coviello 1997; "mild-moderate HCM phenotype and favorable prognosis," Finnish cohorts). R21L — generally favorable (PMID:33642254). V95A — mild phenotype but poor prognosis (Karibe 2001 [PMID UNVERIFIED]). Contemporary registry analyses suggest TNNI3 and TPM1 trend toward higher risk of death/advanced therapies and a combined HF/arrhythmia endpoint than MYH7/MYBPC3 groups.

Morbidity and function

  • Advanced heart failure is the standout CMH3/thin-filament morbidity: 20% vs 7% progression, with survival free of advanced HF 5.2 vs 11.8 years, HR 5.6 (Chumakova 2025).
  • Other morbidity: exertional limitation, AF with stroke risk and anticoagulation burden, ICD implantation and its complications, need for septal reduction therapy (7% in thin-filament vs 17% thick-filament, p=0.025 — lower, consistent with less obstruction in a "thinner" phenotype).
  • Disability outcomes and ICF-coded functional data: not available for CMH3.
  • QoL instruments: KCCQ (HCM standard, used in EXPLORER-HCM and SEQUOIA-HCM), HCMSQ (HCM Symptom Questionnaire), SF-36/EQ-5D generically. No CMH3-specific PRO data.

Disease course / complications

Sudden cardiac death; ventricular tachyarrhythmia; atrial fibrillation → cardioembolic stroke; progressive diastolic then systolic HF; "burnt-out"/end-stage HCM; infective endocarditis (rare, obstructive disease); pregnancy-related decompensation; procedural complications of myectomy/ablation (AV block, need for pacing). Recovery potential: the structural disease is not reversible with current therapy; symptomatic and hemodynamic recovery is achievable and often substantial.

Prognostic factors

  • Established HCM SCD risk factors (used by the 2024 guideline and HCM Risk-SCD): prior cardiac arrest/sustained VT, family history of SCD, unexplained syncope, maximal wall thickness, NSVT, LV apical aneurysm, LVEF <50%, and extensive LGE on CMR (particularly relevant here given 88% LGE prevalence in thin-filament disease). Note the thin-filament cohort had a lower 5-year HCM Risk-SCD score (2.0% vs 3.3%, p=0.002) despite worse HF trajectory — i.e. conventional risk scores may under-call risk in thin-filament HCM, since the scores are wall-thickness-weighted and thin-filament walls are thinner.
  • Genotype as prognostic factor: sarcomere-positive status generally, and the specific TPM1 variant, carry prognostic weight (D175N/R21L favorable vs V95A and malignant novel variants). Polygenic score modifies expressivity (Harper 2021).
  • Prognostic biomarkers: NT-proBNP and hs-troponin (nonspecific but validated in HCM); LGE burden on CMR is arguably the strongest imaging biomarker. No TPM1-specific molecular prognostic biomarker exists.

12. Treatment

There is no CMH3-specific therapy; management follows HCM guidelines, and the mechanistic literature makes a strong case that cardiac myosin inhibition is particularly rational for TPM1 HCM (below). Governing document: PMID:38718139 (2024 AHA/ACC/AMSSM/HRS/PACES/SCMR HCM guideline).

12.1 Pharmacotherapy

Treatment Mechanism Suggested NCIT Modality
Beta blockers (metoprolol, propranolol, bisoprolol) First-line for obstructive and symptomatic HCM; ↓HR, ↑diastolic filling, ↓dynamic gradient NCIT:C15986 Pharmacotherapy + therapeutic_agent NCIT:C61845 Metoprolol (OAK-verified) SMALL_MOLECULE
Non-dihydropyridine CCB (verapamil, diltiazem) Alternative first-line when beta blockers not tolerated; caution in severe obstruction/high gradients NCIT:C15986 + NCIT:C928 Verapamil (OAK-verified) SMALL_MOLECULE
Disopyramide Negative inotrope added to beta blocker/CCB for refractory obstruction NCIT:C15986 + NCIT:C61730 Disopyramide (OAK-verified) SMALL_MOLECULE
Mavacamten Cardiac myosin inhibitor — reduces actin–myosin cross-bridge formation, ↓contractility, ↓LVOT gradient; FDA-approved for symptomatic obstructive HCM; REMS program (echo LVEF monitoring, CYP2C19/CYP3A4 interactions) NCIT:C15986 + NCIT:C174901 Mavacamten (OAK-verified); consider NCIT:C93352 Targeted Therapy SMALL_MOLECULE
Aficamten Next-generation cardiac myosin inhibitor; SEQUOIA-HCM positive NCIT:C15986 + NCIT:C179072 Aficamten (OAK-verified) SMALL_MOLECULE
Anticoagulation (DOAC preferred) AF thromboembolic prophylaxis — Class 1 in HCM regardless of CHA₂DS₂-VASc NCIT:C15986 + agent term SMALL_MOLECULE
Antiarrhythmics (amiodarone, sotalol), rate control AF rhythm/rate control; VT suppression adjunct to ICD NCIT:C15986 SMALL_MOLECULE
Standard HF therapy (ACEi/ARB/ARNI, beta blocker, MRA, SGLT2i) Only in the end-stage/systolic phase — vasodilators and afterload reduction are otherwise contraindicated in obstructive HCM NCIT:C15986 SMALL_MOLECULE
Avoid: dihydropyridine CCB, high-dose diuretics, nitrates, digoxin, other positive inotropes in obstructive disease Worsen gradient — —

Why myosin inhibition is mechanistically apt for CMH3: the TPM1 lesion is loss of the tropomyosin-mediated block on myosin access to actin, producing residual diastolic cross-bridge activity and hypercontractility. Direct myosin inhibition acts immediately downstream. Two independent TPM1 studies show rescue: mavacamten normalized the E62Q hypercontractile phenotype (danicamtiv normalized the E54K hypocontractile DCM phenotype) — PMID:39436707; and in S215L engineered tissue, myosin inhibition produced a "greater relative drop in diastolic stress after acute mavacamten" than in wild type, confirming elevated residual cross-bridge activity as the target — PMID:36896133. These are IN_VITRO / COMPUTATIONAL evidence, not CMH3 clinical trial data, and must be tagged as such.

Pharmacogenomics: CYP2C19 genotype materially affects mavacamten exposure (poor metabolizers require lower dosing; labeled dosing is CYP2C19-informed) — check PharmGKB/CPIC and the FDA label before curating specifics. No TPM1-genotype-guided drug selection exists.

12.2 Advanced therapeutics

  • Gene therapy / gene editing: no clinical program for TPM1. AAV-based approaches are furthest advanced for MYBPC3 HCM (e.g. TN-201) and PKP2 ACM; base/prime editing of dominant missense sarcomere alleles is preclinical. Not available for CMH3.
  • RNA-based therapies (ASO, siRNA): conceptually attractive for a dominant missense allele (allele-selective knockdown), but no TPM1 program identified. Worth recording as a rational-but-absent modality; dismech's antisense_oligonucleotide_therapy module is the relevant reference pattern if one emerges.
  • Cell therapy / immunotherapy: not applicable.
  • Targeted therapy: the cardiac myosin inhibitors are the de facto targeted therapy class; also of note, "Decreasing tropomyosin phosphorylation rescues tropomyosin-induced familial hypertrophic cardiomyopathy" (PMC3789987, MODEL_ORGANISM) identifies tropomyosin phosphorylation as an unexploited target, and transgenic rescue was demonstrated in the α-TM mouse (AJP Heart 2007, doi 10.1152/ajpheart.01341.2006).

12.3 Surgical and interventional

Intervention Role NCIT
Surgical septal myectomy Gold standard for drug-refractory severe LVOTO at experienced centers; low mortality, durable gradient relief Needs OAK lookup — NCIT:C15329 Surgical Procedure or a specific cardiac-surgery term
Alcohol septal ablation Percutaneous alternative in selected anatomy/comorbidity NCIT:C80439 Septal Ablation (OAK-verified)
ICD implantation Secondary prevention (Class 1) and primary prevention by risk stratification NCIT:C80435 Implantable Cardioverter-Defibrillator Placement / NCIT:C93238 device (OAK-verified)
Heart transplantation End-stage/burnt-out HCM or intractable arrhythmia NCIT:C15246 Heart Transplantation (OAK-verified)
Mitral valve intervention; AF catheter ablation; LAA occlusion Adjunctive —

Guideline framing (2024): "Invasive septal reduction therapies (surgical septal myectomy and alcohol septal ablation), when performed by experienced HCM teams at dedicated centers, can provide safe and effective symptomatic relief for patients with drug-refractory or severe outflow tract obstruction"; and following mavacamten's approval the guideline "now includes it as an option before more invasive therapies when first-line treatments like beta blockers or calcium channel blockers are not effective."

12.4 Supportive, rehabilitative, lifestyle

  • Genetic counseling — NCIT:C15240 Genetic Counseling (OAK-verified); modality BEHAVIORAL.
  • Cardiac rehabilitation / supervised exercise — the 2024 guideline substantially liberalized exercise and return-to-play recommendations relative to prior guidance, endorsing an expanded role for exercise with shared decision-making. Suggested NCIT:C15315 Rehabilitation / NCIT:C15302 Physical Therapy.
  • Multidisciplinary HCM center care and shared decision-making — explicit guideline recommendation: patients "should be engaged in shared decision making to develop a care plan, with multidisciplinary HCM centers helping to confirm diagnosis, facilitate genetic testing, and guide advanced treatment options." NCIT:C15747 Supportive Care.
  • Volume/hydration management, avoidance of dehydration and precipitants; pregnancy planning and specialized peripartum care.

12.5 Experimental treatments / clinical trials

  • NCT03470545 — EXPLORER-HCM, phase 3, mavacamten in symptomatic obstructive HCM; primary and all secondary endpoints met (p≤0.0006).
  • NCT03723655 — MAVA-LTE, long-term safety extension for EXPLORER-HCM/MAVERICK-HCM completers.
  • NCT05186818 — SEQUOIA-HCM, phase 3, aficamten; "aficamten compared with placebo led to significant improvements in peak oxygen uptake, symptoms, and health status and reductions in LVOT gradients at rest and with Valsalva maneuver"; benefit extended to patients with mild symptoms (PMC12539928).
  • MAVERICK-HCM (nonobstructive HCM, mavacamten); ODYSSEY-HCM and other nonobstructive-HCM myosin-inhibitor programs; MYBPC3 gene-therapy trials (not applicable to TPM1).
  • No CMH3- or TPM1-specific interventional trial exists. Trials enroll by phenotype (obstructive/nonobstructive HCM), not genotype.

12.6 Treatment strategy / algorithm

  1. Confirm HCM and exclude phenocopies (CMR, Fabry/amyloid/Danon workup as indicated).
  2. Genetic testing + cascade screening; genetic counseling.
  3. SCD risk stratification → ICD decision.
  4. Obstructive + symptomatic: beta blocker → non-DHP CCB → add disopyramide or cardiac myosin inhibitor → septal reduction therapy (myectomy or alcohol ablation).
  5. Nonobstructive + symptomatic: beta blocker/CCB, diuretics cautiously, treat AF, consider myosin inhibitor per emerging evidence.
  6. AF: anticoagulate (Class 1), rate/rhythm control, consider ablation.
  7. End-stage (LVEF <50%): guideline-directed HF therapy → advanced therapies/transplant.
  8. Lifelong surveillance; family surveillance of G+/P− relatives.

Combination therapy is the norm (beta blocker + disopyramide; beta blocker + myosin inhibitor; anticoagulant + rate control). Personalized medicine: currently genotype informs diagnosis, family screening, and prognostic counseling rather than drug choice; CYP2C19 genotype informs mavacamten dosing; the force-homeostasis framework (PMID:39436707) is the first credible basis for genotype-directed modulator selection (myosin inhibitor for hypercontractile variants, myotrope for hypocontractile ones) — currently preclinical.

13. Prevention

  • Primary prevention (of disease occurrence): not possible for a monogenic dominant disorder. Reproductive prevention options: preimplantation genetic testing for monogenic disease (PGT-M) and prenatal diagnosis for a known familial TPM1 variant; genetic counseling for 50% transmission risk. Prevention of phenotype in carriers is an active research question — the modifiable-risk-factor finding (diastolic BP; Harper 2021) and the concept of pre-emptive myosin inhibition in G+/P− carriers are the leading directions; neither is guideline-endorsed.
  • Secondary prevention (early detection): cascade genetic testing of first-degree relatives plus serial ECG/echo surveillance of genotype-positive relatives — the highest-value intervention in CMH3, justified by 46% 15-year penetrance and the ECG-precedes-hypertrophy pattern (PMID:32731933). Targeted founder-variant screening is defensible in Finland (PMID:22462493). Pre-participation athlete screening is the population-level analogue.
  • Tertiary prevention (of complications): ICD for SCD; anticoagulation for AF-related stroke; septal reduction/myosin inhibition to prevent HF progression; endocarditis and precipitant avoidance; specialized pregnancy management; treatment of hypertension and obesity to limit expressivity.
  • Immunization: not disease-specific; standard influenza/COVID/pneumococcal vaccination is reasonable in patients with structural heart disease. Not a CMH3 prevention strategy.
  • Risk stratification: HCM Risk-SCD / 2024 AHA-ACC risk-marker approach, with the caveat that thin-filament HCM had a lower calculated 5-year SCD score despite worse HF trajectory (Chumakova 2025) — potential under-estimation.
  • Genetic counseling: Class 1; covers 50% transmission, incomplete/age-dependent and sex-modified penetrance, extreme intrafamilial variability, PGT-M/prenatal options, and insurance/psychosocial implications. NCIT:C15240.
  • Behavioral interventions: BP and weight control; avoidance of dehydration and known precipitants; individualized (and, per 2024, substantially liberalized) exercise prescription with shared decision-making.
  • Public health / environmental interventions: not applicable beyond athlete screening programs and public AED/CPR availability, which reduce SCD case fatality rather than disease incidence.

14. Other Species / Natural Disease

Taxonomy and orthologs

  • Homo sapiens — NCBITaxon:9606 (the disease entity).
  • Orthologs of TPM1 exist across vertebrates and are highly conserved (tropomyosin is among the most conserved cytoskeletal/contractile proteins): Mus musculus Tpm1 (NCBITaxon:10090), Rattus norvegicus Tpm1 (NCBITaxon:10116), Danio rerio tpma (NCBITaxon:7955). Specific NCBI Gene IDs should be looked up before curation rather than asserted here.

Natural disease in other species

  • No naturally occurring TPM1-associated hypertrophic cardiomyopathy has been reported in any non-human species. A targeted OMIA search returned feline HCM loci in MYBPC3 (Maine Coon A31P, Ragdoll R820W; OMIA:000515-9685), MYH7 (OMIA:002212-9685), ALMS1 (OMIA:002316-9685), and TNNT2 — but no TPM1 entry for cat or dog. Feline HCM is the closest naturally occurring animal counterpart of human HCM: HCM prevalence was highest in Maine Coon A31P homozygotes with penetrance increasing with age, and the A31P/R820W variants are breed-restricted (2013 survey).
  • Breed (VBO): not applicable to TPM1; VBO terms for Maine Coon and Ragdoll would apply to the MYBPC3 feline entity, not CMH3.
  • Veterinary relevance: feline HCM is a major cause of morbidity/mortality in cats and a well-used spontaneous large-animal model of human HCM pathophysiology — but as a gene-non-identical comparator for CMH3.

Comparative biology

  • Comparative pathology: the myocyte hypertrophy / myofibrillar disarray / interstitial fibrosis triad is conserved across human HCM, feline HCM, and the TPM1 transgenic rodents (§15) — supporting that the tissue-level program is species-general.
  • Evolutionary conservation of mechanism: tropomyosin's period/coiled-coil architecture, its actin-groove positioning, and the three-state steric-blocking regulatory mechanism are conserved from invertebrates to mammals; residues 175/180 lie in a conserved troponin-T-interaction region. This conservation is what makes rodent transgenesis informative, and it is also why the human-vs-rodent isoform and troponin-partner context matters (see the isoform caveat in PMID:10900175).
  • Zoonotic potential / cross-species transmission: not applicable — genetic, non-communicable.

15. Model Organisms

15.1 Transgenic mouse — α-TM180 (Glu180Gly): the flagship in vivo model

A familial hypertrophic cardiomyopathy alpha-tropomyosin mutation causes severe cardiac hypertrophy and death in mice. J Mol Cell Cardiol. 2001. PMID:11603924 (Prasad/Wieczorek-lab lineage; the first in vivo transgenic systems for thin-filament HCM mutations).

  • Construct: cardiac-restricted expression of α-tropomyosin with Glu180Gly, a substitution "which occurs in a troponin T binding region."
  • Phenotype: initial pathologic changes — ventricular concentric hypertrophy, fibrosis, and atrial enlargement — detected within 1 month; progressive worsening with death between 4 and 5 months (a companion review states mice "die by 6 months of age" — note this minor discrepancy across sources and cite the primary paper).
  • Physiology: significant diastolic dysfunction; myofilaments show increased thin-filament activation through enhanced Ca²⁺ sensitivity of steady-state force.
  • Histology: concentric LV hypertrophy, interstitial fibrosis, myocyte disarray.
  • Contrast with the D175N mouse, which has normal heart weight-to-body weight ratio with only patchy areas of myocyte hypertrophy — i.e. the mouse models recapitulate the human genotype–severity gradient (E180G ≫ D175N), which is a genuinely strong validity argument for this model pair.

15.2 Transgenic rat — D175N vs E180G

α-Tropomyosin mutations Asp175Asn and Glu180Gly affect cardiac function in transgenic rats in different ways. Am J Physiol Regul Integr Comp Physiol. 2004; doi 10.1152/ajpregu.00620.2003. Key results: "Ca²⁺ sensitivity of cardiac skinned-fiber preparations from animals with mutation Asp175Asn, but not Glu180Gly, was decreased," and "elevated frequency and amplitude of spontaneous Ca²⁺ waves were detected only in cardiomyocytes from animals with mutation Asp175Asn." A companion paper analyzed autonomic cardiac control/HRV variability in these rats (Biomed Tech 2007, doi 10.1515/BMT.2007.010). Important nuance: the rat D175N Ca²⁺-sensitivity direction is opposite to the human in-vitro motility result (PMID:10900175) — a real cross-system discordance, and a good candidate for a dismech HUMAN_MODEL_MISMATCH discussion.

15.3 Rescue / mechanism-probing models

  • Rescue of tropomyosin-induced familial hypertrophic cardiomyopathy mice by transgenesis. Am J Physiol Heart Circ Physiol. 2007; doi 10.1152/ajpheart.01341.2006.
  • Decreasing Tropomyosin Phosphorylation Rescues Tropomyosin-induced Familial Hypertrophic Cardiomyopathy (PMC3789987) — identifies tropomyosin phosphorylation as a modifiable disease node.
  • Functional effects of a tropomyosin mutation linked to FHC contribute to maladaptation during acidosis (PMC3035739) — the gene–environment (acidosis) model.

15.4 Human cellular models (the current workhorses)

  • Patient-derived hiPSC-CMs, TPM1-D175N (Finnish founder): "displayed pathological phenotypes of HCM with differences in cellular size, Ca²⁺ handling, and electrophysiological properties" relative to MYBPC3-mutant lines — Ojala M, et al., PMC4707351. Model type: iPSC-derived cardiomyocyte, patient-specific.
  • Isogenic CRISPR-edited hiPSC-CM + 3D engineered heart tissue (EHT) for S215L, E62Q, E54K — Halder et al., PMID:36896133 and PMID:39436707. Readouts: isometric twitch force, relaxation kinetics, diastolic stiffness, cardiomyocyte volume, hypertrophic marker qPCR, acute drug response (mavacamten, danicamtiv). This platform is currently the best available human-context model of CMH3.
  • Reconstituted in-vitro systems: recombinant human α-tropomyosin with N-terminal Ala-Ser extension (to mimic acetylation) + purified native human cardiac troponin, in-vitro motility assay (PMID:10900175); actin-bound tropomyosin thermal unfolding (PMID:15454401); ATPase-cycle strand-position measurements (PMID:21376702).
  • Computational models: Markov-state myofilament models and all-atom MD of the actin–Tm–Tn complex; "Predicting Effects of Tropomyosin Mutations on Cardiac Muscle Contraction through Myofilament Modeling" (Front Physiol 2016).

15.5 Genetic model types available

Transgenic overexpression (mouse, rat — the historical standard for TPM1); CRISPR knock-in isogenic hiPSC lines (current standard for human context). Knock-in mouse models of specific TPM1 HCM alleles at the endogenous locus are less prominent in the literature than the transgenic lines — worth verifying against MGI/IMSR before asserting availability. Conditional and humanized Tpm1 models: not identified.

15.6 Phenotype recapitulation and limitations

Recapitulated: concentric/asymmetric hypertrophy, interstitial fibrosis, myocyte disarray, atrial enlargement, diastolic dysfunction, increased myofilament Ca²⁺ sensitivity, premature death (E180G mouse), and — importantly — the variant-severity ordering (E180G > D175N).

Limitations (candidate HUMAN_MODEL_MISMATCH items): 1. Transgenic overexpression does not reproduce the human 1:1 mutant:wild-type allelic stoichiometry, and Thierfelder's own hypothesis was that stoichiometry itself matters. 2. Isoform/partner context is decisive and species-divergent. PMID:10900175 explicitly concludes: "The results using human cardiac regulatory proteins reveal different effects of the HCM mutations in tropomyosin compared to studies using heterologous systems" — i.e. non-human/heterologous systems can give the wrong answer for TPM1. 3. Direction-of-effect discordance: rat D175N showed decreased skinned-fiber Ca²⁺ sensitivity while human reconstituted filaments showed increased Ca²⁺ sensitivity. 4. Rodent heart rate, β-MHC/α-MHC isoform composition, and Ca²⁺-handling kinetics differ fundamentally from human, limiting translation of relaxation/energetics phenotypes. 5. hiPSC-CMs are immature (fetal-like sarcomere, ion channel, and metabolic profile), lack chronic hemodynamic loading, and cannot model LVOT obstruction, arrhythmic SCD, or decades-long fibrotic remodeling. 6. No animal model reproduces sudden cardiac death as the human clinical endpoint, nor human penetrance/expressivity variability. 7. No natural animal TPM1 HCM exists to serve as a spontaneous-disease comparator.

15.7 Research applications

Thin-filament regulatory mechanism and Ca²⁺-sensitivity measurement; tropomyosin mechanics (stiffness/persistence length); genotype-specific contractile phenotyping (hyper- vs hypocontractile); hypertrophic gene-program induction; drug screening and acute pharmacologic rescue (mavacamten, danicamtiv, tropomyosin-phosphorylation modulation); VUS reclassification pipelines (the S215L precedent); gene–environment stress testing (acidosis).

15.8 Model resources

MGI (mouse Tpm1), RGD (rat Tpm1), ZFIN (tpma), Alliance of Genome Resources, IMSR/MMRRC/EMMA for strain availability, Cellosaurus for hiPSC lines. Specific strain and line accessions should be pulled from MGI/IMSR at curation time rather than inferred.

Curation notes for the dismech entry

Confirmed correct in the existing draft: disease_term MONDO:0007267 / label hypertrophic cardiomyopathy 3 (OAK-verified), category: Genetic, synonyms, parents: [Hypertrophic Cardiomyopathy, Genetic Disorder].

Module conformance candidates (declare with conforms_to, substituting the TPM1-specific driver): - cardiomyopathy_maladaptive_remodeling — the structural/contractile HCM module; key target #Ventricular Remodeling. Primary conformance target for this entry. - fibrotic_response — at the myocardial-fibrosis node (88% LGE; replacement fibrosis on histology). - cardiac_ion_channel_repolarization — use with care. That module is explicitly scoped to inherited arrhythmia syndromes in structurally normal hearts; CMH3 arrhythmia is substrate-driven (fibrosis/disarray). A partial conformance at the #Arrhythmogenic Substrate and Triggered Activity node is defensible for the D175N spontaneous-Ca²⁺-wave arm (rat data), but should be flagged rather than asserted broadly.

Suggested mechanistic_hypotheses groups: 1. force_homeostasis_hcm_dcm_divergence (status EMERGING) — hypercontractility → hypertrophy vs hypocontractility → dilation, anchored on PMID:39436707. Edges from the hypercontractility node to the hypertrophy node opt in. 2. camkii_hdac4_hypertrophic_signaling (status EMERGING) — the Ca²⁺/CaMKII → HDAC4 route from myofilament Ca²⁺ sensitization to a transcriptional program; anchored on the TPM1 E181K RCM work (PMC12818787), and explicitly extrapolated from a different TPM1 phenotype — mark as such. 3. tropomyosin_phosphorylation_as_target (status EMERGING) — PMC3789987, MODEL_ORGANISM.

Suggested discussions entries: - kind: HUMAN_MODEL_MISMATCH — human reconstituted filaments show increased Ca²⁺ sensitivity for D175N (PMID:10900175) while transgenic rat skinned fibers show decreased Ca²⁺ sensitivity (AJP Regul 2004); and PMID:10900175 states directly that heterologous systems give different answers. Propose: isogenic human hiPSC-CM/EHT measurement of D175N Ca²⁺ sensitivity with human cardiac troponin. - kind: KNOWLEDGE_GAP — no CMH3-specific transcriptomic, proteomic, metabolomic, or single-cell dataset; no CMH3-specific survival curve; no TPM1-genotype-stratified myosin-inhibitor trial data; germline mosaicism unassessed; no epigenomic data. - kind: KNOWLEDGE_GAP — conventional wall-thickness-weighted SCD risk scores may systematically under-call risk in thin-filament HCM (5-y score 2.0% vs 3.3% despite worse HF trajectory; Chumakova 2025), yet the classical literature reports "high incidence of sudden death" for α-tropomyosin mutations (PMID:7898523). This tension is unresolved and clinically consequential.

Evidence-source tagging reminders: PMID:8205619, 7898523, 7729014, 22462493, 15000344, 32731933, 33642254, 12651045, 38718139, Chumakova 2025, Coviello 1997 → HUMAN_CLINICAL. PMID:11603924, AJP Regul 2004, AJP Heart 2007, PMC3789987 → MODEL_ORGANISM. PMID:10900175, 9109674, 15454401, 21376702, 22794249, PMC4707351, PMC3035739 → IN_VITRO. PMID:36896133 and 39436707 are mixed (MD/Markov modeling + hiPSC-CM/EHT experiments) — split into separate evidence items, one COMPUTATIONAL and one IN_VITRO, per the repo rule that each item carries a single evidence_source. PMID:39132495 (ClinGen) and cardiodb ACGV burden statistics → OTHER (expert-panel consensus / aggregate case–control resource).

NEC preflight result (per CLAUDE.md §2b): clean. MONDO:0007267's def: and logical definition name TPM1 (RO:0004003 HGNC:12010); the OMIM xref is 115196, matching every source used; and the synonyms CMH3 / TPM1 hypertrophic cardiomyopathy are the exact labels the literature keyed off. No gene-frequency or OMIM mismatch. However, CMH3 sits in a high-NEC-risk class — it is a numbered series (CMH1–CMH27) and the gene is pleiotropic across four cardiomyopathy phenotypes. Two concrete confusion traps to guard against: (i) CMH3 vs other numbered CMH entries (CMH1/MYH7, CMH2/TNNT2, CMH4/MYBPC3 …); (ii) CMH3 vs the TPM1 allelic non-HCM entities — CMD1Y, LVNC9, and TPM1 restrictive cardiomyopathy. Note especially that E180G (HCM) and E181K (restrictive) are adjacent residues in the same gene — any DR report mixing these must be treated as suspect.

Structured-source citations available for this entry: an ORPHA: record for familial HCM and, most valuably, a CGGV: ClinGen Gene-Disease Validity record for TPM1–HCM (Definitive) — that assertion row is a cleaner, snippet-validatable evidence anchor for the gene–disease claim than the PMID:39132495 abstract. Run just clingen-list / just clingen-rebuild --id CGGV:<id> to locate and cache it.

Sources