Hypertrophic Cardiomyopathy 25

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Classifications

Harrison's Part

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Inheritance

1

Autosomal Dominant HP:0000006

Where a mode of inheritance has been recorded for TCAP cardiomyopathy it is autosomal dominant heterozygous transmission of a missense (or, in one report, frameshift) allele. Segregation data are thin: a single small Portuguese family demonstrated co-segregation of the p.C57W allele, and the 2025 frameshift report identified the variant in the proband's family. Contrast with the TCAP skeletal-muscle disease (LGMD R7/2G), which is autosomal recessive and biallelic loss of function.

Autosomal dominant inheritance

Show evidence (2 references)

CGGV:assertion_c35abc20-c04c-49ec-af02-1bd270b0b50b-2022-09-14T160000.000Z SUPPORT Other

ClinGen records autosomal dominant inheritance for the TCAP-HCM gene-disease relationship, alongside the Disputed validity classification.

PMID:32565061 SUPPORT Human Clinical

"Family members were screened for this new mutation and a co-segregation pattern was detected."

The only published co-segregation observation for a TCAP HCM allele. PARTIAL because the family is explicitly described as small, so the segregation evidence is weak on its own.

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Mechanistic Hypotheses

1

Z-disc stretch-sensor gain-of-interaction model

tcap_zdisc_stretch_sensor_gain_of_interaction EMERGING

Evidence balance 2 support 1 refute

The only mechanistic model proposed for TCAP-HCM holds that the hypertrophic and dilated phenotypes are separated by the *direction* of the binding change within the titin/telethonin/MLP Z-disc stretch sensor: the two HCM-associated missense alleles (T137I, R153H) augmented telethonin's interaction with titin and calsarcin-1 in yeast two-hybrid and GST pull-down assays, whereas the DCM-associated alleles impaired binding to MLP, titin, and calsarcin-1. Because calsarcin tethers calcineurin — a canonical pro-hypertrophic phosphatase — to the Z-disc, a gain of telethonin-calsarcin interaction is the proposed route from a Z-disc scaffolding change to hypertrophic growth. This remains EMERGING and contested: the assays were qualitative, no downstream calcineurin readout was measured in the original work, no independent group has replicated the binding result, and ClinGen states outright that the disease mechanism is unknown.

Pathograph links

Telethonin Z-Disc Titin-Capping and Stretch-Sensor Perturbation -> Altered Z-Disc Signalosome Output UNKNOWN Proposed, not demonstrated: the causal step from altered telethonin binding to a changed hypertrophic signalling output has never been measured in cardiomyocytes carrying an HCM allele.

Altered Z-Disc Signalosome Output -> Cardiomyocyte Hypertrophy INDIRECT UNKNOWN INTERMEDIATES

Show evidence (3 references)

PMID:15582318 SUPPORT In Vitro

"It was demonstrated by the qualitative assays that the HCM-associated mutations augment the ability of Tcap to interact with titin and calsarcin-1, whereas the DCM-associated mutations impair the interaction of Tcap with MLP, titin, and calsarcin-1."

The primary in vitro basis for the gain-of-interaction model and for the HCM-versus-DCM directional split. Evidence source is IN_VITRO because the result comes from yeast two-hybrid and GST pull-down competition assays.

PMID:15582318 SUPPORT Other

"These observations suggest that the difference in clinical phenotype (HCM or DCM) may be correlated with the property of altered binding among the Z-disc components."

The authors state the hypothesis in their own hedged terms ("may be correlated"), which is why this group is EMERGING rather than CANONICAL. Evidence source is OTHER because the quote is the paper's interpretive conclusion rather than a measurement.

CGGV:assertion_c35abc20-c04c-49ec-af02-1bd270b0b50b-2022-09-14T160000.000Z REFUTE Other

"The mechanism for disease is unknown."

ClinGen's expert-panel judgement that no disease mechanism is established for TCAP-HCM. Recorded as REFUTE against the claim that this model is settled; it is the reason the hypothesis is not marked CANONICAL.

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Discussions and Knowledge Gaps

4

Is TCAP a genuine hypertrophic cardiomyopathy gene at all, or is CMH25 an artefact of pre-genomic candidate-gene sequencing?

CONTROVERSY OPEN tcap_hcm_gene_disease_validity_disputed

Attached to

pathophysiology#Telethonin Z-Disc Titin-Capping and Stretch-Sensor Perturbation

ClinGen's Hereditary Cardiovascular Disease GCEP downgraded TCAP-HCM from Limited to Disputed in September 2022. The case-level base is roughly eight probands over four publications; no reported variant has functional support; one variant (2 probands) is common in the population; two probands carried a second variant (a pathogenic TNNI3 variant, and a MYBPC3 VUS). A dedicated 2023 TCAP screen of 40 Iranian cardiomyopathy patients found no pathogenic allele. Dismech curates the entity because MONDO:0011843 exists and clinical panels still return TCAP variants, but the whole pathograph in this entry is conditional on the association being real, and every node is tagged HYPOTHETICAL or PROVISIONAL accordingly.

Proposed experiments

Case-control rare-variant burden test for TCAP in hypertrophic cardiomyopathy

exp_tcap_hcm_case_control_burden

Compare the burden of rare TCAP variation in large sequenced hypertrophic cardiomyopathy cohorts against ancestry-matched population reference data (gnomAD), with the definitive-gene carriers excluded so a residual TCAP signal is not confounded by a co-occurring sarcomere variant.

Supporting outcome

A significant excess of rare TCAP variation in cases would move the gene-disease relationship above Disputed.

Refuting outcome

Absence of excess burden at adequate power would support refuting the association outright.

Isogenic human cardiomyocyte allele series for the reported TCAP HCM variants

exp_tcap_hcm_isogenic_allele_series

Knock the reported alleles (T137I, R153H, C57W, p.Glu12fs) into a common hiPSC background and phenotype the derived cardiomyocytes and engineered heart tissues for hypertrophy, sarcomere organisation, and relaxation.

Supporting outcome

A reproducible hypertrophic or diastolic phenotype attributable to the allele would supply the missing functional evidence.

Refuting outcome

Indistinguishable phenotype from isogenic wild type would argue the alleles are benign.

Contemporary re-sequencing of the published TCAP HCM probands

exp_tcap_hcm_rephenotyping_published_probands

Re-analyse the originally reported probands with current cardiomyopathy panels or genome sequencing to establish whether a better-supported variant in another gene explains each case.

Refuting outcome

Recovery of a definitive-gene variant in most probands would collapse the residual case-level evidence for TCAP.

Show evidence (2 references)

CGGV:assertion_c35abc20-c04c-49ec-af02-1bd270b0b50b-2022-09-14T160000.000Z SUPPORT Other

"As a result of this reevaluation, the classification changed from LIMITED to DISPUTED."

The classification change that frames this controversy.

PMID:37752589 SUPPORT Human Clinical

"These findings suggest that the TCAP gene pathogenic mutations might not be a common cause of cardiomyopathies among Iranian patients."

Independent negative cohort evidence contributing to the dispute.

What, mechanistically, does an HCM-associated TCAP allele do to the cardiomyocyte downstream of the Z-disc?

KNOWLEDGE GAP OPEN tcap_hcm_mechanism_unknown

Attached to

pathophysiology#Altered Z-Disc Signalosome Output

The only mechanistic data are qualitative yeast two-hybrid and GST pull-down results from 2004 showing augmented telethonin binding to titin and calsarcin-1. Nothing downstream has been measured: no calcineurin activity, no NFAT nuclear translocation, no hypertrophic gene program, no sarcomere-organisation phenotype, no contractile or relaxation measurement in any TCAP-HCM cell, tissue, or animal model. ClinGen states plainly that the mechanism is unknown. The Z-disc signalosome node in this entry is therefore a placeholder that names the proposed route rather than a curated mechanism.

Proposed experiments

Quantitative binding measurement of mutant telethonin with its Z-disc partners

exp_tcap_quantitative_zdisc_binding

Replace the original qualitative yeast two-hybrid and pull-down assays with quantitative affinity measurements (isothermal titration calorimetry or surface plasmon resonance) of mutant versus wild-type telethonin against titin Z1Z2, muscle LIM protein, and calsarcin-1.

Supporting outcome

Reproducible, direction-consistent affinity changes would substantiate the gain-of-interaction model.

Refuting outcome

Affinities indistinguishable from wild type would remove the only mechanistic support for the model.

Calcineurin-NFAT signalling readout in TCAP knock-in cardiomyocytes

exp_tcap_calcineurin_nfat_readout

Measure calcineurin activity, NFAT nuclear translocation, and hypertrophic marker gene expression in cardiomyocytes carrying knock-in TCAP HCM alleles, closing the untested step between altered calsarcin binding and hypertrophic growth.

Supporting outcome

Allele-dependent calcineurin-NFAT activation would convert the placeholder signalosome node into a curated mechanism.

Sarcomere ultrastructure and relaxation phenotyping in TCAP engineered heart tissue

exp_tcap_sarcomere_and_relaxation_phenotyping

Characterise Z-disc ultrastructure by electron microscopy and measure active and passive mechanics in engineered heart tissue carrying each reported allele, to test whether the human diastolic phenotype is reproduced in vitro.

Show evidence (2 references)

CGGV:assertion_c35abc20-c04c-49ec-af02-1bd270b0b50b-2022-09-14T160000.000Z SUPPORT Other

"The mechanism for disease is unknown."

Expert-panel confirmation that no mechanism is established.

CGGV:assertion_c35abc20-c04c-49ec-af02-1bd270b0b50b-2022-09-14T160000.000Z SUPPORT Other

"None of these variants have functional evidence in support of pathogenicity."

The absence of allele-level functional data is the concrete gap.

Does the telethonin-knockout mouse model the human TCAP hypertrophic phenotype, given that it is a loss-of-function model that produces stress-induced heart failure rather than hypertrophic cardiomyopathy?

HUMAN MODEL MISMATCH OPEN tcap_mouse_knockout_versus_human_hcm

Attached to

pathophysiology#Impaired Myocardial Adaptation to Biomechanical Stress

The Tcap-null mouse is the only in vivo cardiac model, and it points the opposite way from the human cardiac claim on three counts. First, direction of effect: the mouse lacks telethonin entirely, whereas the human HCM alleles are heterozygous missense changes reported to *augment* Z-disc binding. Second, phenotype: the mouse has a structurally and functionally normal heart at baseline and decompensates into heart failure with cardiomyocyte apoptosis only after biomechanical stress — it does not develop hypertrophic cardiomyopathy. Third, the same study explicitly refutes the structural premise that telethonin is indispensable for titin anchorage. Any inference from this model to CMH25 pathogenesis therefore requires an unstated and unverified assumption that loss and gain of Z-disc interaction converge on the same disease.

Proposed experiments

Missense knock-in rather than null mouse model of TCAP cardiomyopathy

exp_tcap_missense_knockin_mouse

Generate mice carrying the human T137I, R153H, or C57W allele in place of a null allele and phenotype for left ventricular hypertrophy, septal geometry, and diastolic function.

Supporting outcome

A hypertrophic phenotype in a missense knock-in would establish allele-appropriate in vivo modelling of CMH25.

Refuting outcome

A normal heart in the knock-in, in contrast to the stressed null, would show the null mouse does not model the human allele.

Head-to-head stress phenotyping of null versus missense knock-in genotypes

exp_tcap_null_versus_knockin_stress_comparison

Subject Tcap-null and missense knock-in animals to identical biomechanical stress protocols and compare hypertrophy, apoptosis, and heart-failure endpoints, to test whether loss and altered interaction converge.

p53-dependent apoptosis assessment in human TCAP-variant myocardium

exp_tcap_human_myocardium_p53_apoptosis

Examine explanted or biopsy myocardium from a TCAP variant carrier for nuclear telethonin accumulation, p53 stabilisation, and cardiomyocyte apoptosis, to test whether the murine mechanoptosis route operates in the human disease.

Show evidence (2 references)

PMID:21799151 SUPPORT Model Organism

"Telethonin knockout mice do not reveal defective heart development or heart function under basal conditions, but develop heart failure following biomechanical stress"

The model phenotype is stress-induced heart failure, not hypertrophic cardiomyopathy — the core of the mismatch.

PMID:15582318 SUPPORT In Vitro

"the HCM-associated mutations augment the ability of Tcap to interact with titin and calsarcin-1"

The human HCM alleles are reported as gain-of-interaction, the opposite direction from the null mouse.

What is the prevalence and penetrance of TCAP-attributed hypertrophic cardiomyopathy?

KNOWLEDGE GAP OPEN tcap_hcm_prevalence_and_penetrance_unknown

Neither is known, and neither can be estimated while the association is Disputed. The only figures available are clinic-cohort yields (4 of 389, and 1 of 239 myofilament-negative probands), which ClinGen has shown are inflated by at least one common population variant. No population-based carrier frequency, no penetrance estimate, and no natural-history series exist for CMH25.

Proposed experiments

Population-biobank carrier frequency and imaging penetrance for TCAP alleles

exp_tcap_biobank_carrier_penetrance

Identify carriers of the reported TCAP hypertrophic-cardiomyopathy alleles in a population biobank with cardiac magnetic resonance imaging and quantify how many show left ventricular hypertrophy, giving an ascertainment-free penetrance estimate.

Refuting outcome

A high carrier frequency with no imaging phenotype would argue the alleles are benign population variation.

Multi-registry aggregation of TCAP variant carriers with hypertrophic cardiomyopathy

exp_tcap_registry_natural_history

Pool TCAP variant carriers across international hypertrophic cardiomyopathy registries with standardised phenotyping and follow-up to assemble a natural-history series large enough to describe onset, outcome, and arrhythmic risk.

Show evidence (1 reference)

CGGV:assertion_c35abc20-c04c-49ec-af02-1bd270b0b50b-2022-09-14T160000.000Z SUPPORT Other

"Furthermore, 1 variant (2 probands) is common in the population (Bos et al, 2006, PMID 16352453), and 2 co-occurred with other variants"

Shows why the published cohort yields cannot be converted into a prevalence estimate.

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Pathophysiology

7

Telethonin Z-Disc Titin-Capping and Stretch-Sensor Perturbation

TCAP encodes telethonin, a small Z-disc protein that assembles with the N-terminal immunoglobulin domains of two antiparallel titin molecules, capping the Z-disc end of titin and nucleating a signalosome that also contains muscle LIM protein (MLP/CSRP3), the calsarcins, and — as more recently shown — nesprin-2 and FHL-2. This complex, not the contractile filaments, is the proposed proximal lesion: the HCM-associated alleles reported to date (T137I, R153H, C57W, and one p.Glu12fs frameshift) change how telethonin engages its Z-disc partners rather than removing the protein from the sarcomere. The trigger is deliberately tagged HYPOTHETICAL: no functional assay has established pathogenicity for any of these alleles.

Z-disc stretch-sensor gain-of-interaction model

Cardiomyocyte CL:0000746

TCAP hgnc:11610

Detection of muscle stretch GO:0035995 ⚠ ABNORMAL

titin binding GO:0031432 ⚠ ABNORMAL structural constituent of muscle GO:0008307 ⚠ ABNORMAL

Z disc GO:0030018

Myocardium UBERON:0002349

Downstream

Altered Z-Disc Signalosome Output Proposed, not demonstrated: the causal step from altered telethonin binding to a changed hypertrophic signalling output has never been measured in cardiomyocytes carrying an HCM allele.

Impaired Myocardial Adaptation to Biomechanical Stress Supported only by loss-of-function model organisms, whose relevance to the human missense alleles is unresolved (see the HUMAN_MODEL_MISMATCH discussion).

Show evidence (8 references)

PMID:15582318 SUPPORT Other

"The Z-disc plays a role in establishing the mechanical coupling of sarcomeric contraction and stretching, with the titin/Tcap/MLP complex serving as a mechanical stretch sensor."

States the normal Z-disc stretch-sensor role of the titin/telethonin/MLP complex whose perturbation is the proposed primary lesion. Evidence source is OTHER because the quote is the paper's background framing.

PMID:16352453 SUPPORT Other

"TTN-encoded titin, CSRP3-encoded muscle LIM protein, and TCAP-encoded telethonin are Z-disc proteins essential for the structural organization of the cardiac sarcomere and the cardiomyocyte's stretch sensor."

Independent statement, from the HCM cohort study itself, that telethonin belongs to the Z-disc structural and stretch-sensing apparatus rather than the myofilament. Evidence source is OTHER because it is background framing.

PMID:21799151 SUPPORT Other

"hypothesized to assemble in a palindromic way with the N-terminal portion of titin and to constitute a signalosome participating in the process of cardiomechanosensing"

Supplies the structural detail of the titin-capping arrangement and the signalosome framing. Evidence source is OTHER because the quote is the study's stated rationale rather than its result.

+ 5 more references

Altered Z-Disc Signalosome Output

The proposed intracellular consequence of a mis-binding telethonin is a change in the signalling output of the Z-disc, not a change in force production. Telethonin binds calsarcin, and calsarcin tethers the pro-hypertrophic phosphatase calcineurin to the Z-disc; the two HCM-associated alleles increased telethonin's affinity for titin and calsarcin-1 in vitro, which is the proposed route to a hypertrophic transcriptional program. No calcineurin, NFAT, or hypertrophy readout has been measured in any TCAP-HCM model, so this node is a mechanistic placeholder held together by protein-interaction data alone.

Z-disc stretch-sensor gain-of-interaction model

Cardiomyocyte CL:0000746

Detection of muscle stretch GO:0035995 ⚠ ABNORMAL Response to mechanical stimulus GO:0009612 ⚠ ABNORMAL

Z disc GO:0030018

Downstream

Cardiomyocyte Hypertrophy

Show evidence (2 references)

PMID:15582318 SUPPORT Other

"Tcap interacts with the calsarcin, which tethers the calcineurin to the Z-disc."

Establishes the telethonin-calsarcin-calcineurin tether that makes a hypertrophic signalling output mechanistically plausible. Evidence source is OTHER because the statement is background, not a result of this study.

PMID:15582318 SUPPORT In Vitro

"the HCM-associated mutations augment the ability of Tcap to interact with titin and calsarcin-1"

The measured binding change that the signalling hypothesis rests on. PARTIAL because increased calsarcin binding was not followed through to any calcineurin or hypertrophy readout.

Impaired Myocardial Adaptation to Biomechanical Stress

The best-characterised in vivo consequence of losing telethonin is not a structural Z-disc collapse but a failure of stress adaptation. Telethonin knockout mice have normal hearts at baseline — other titin anchorage routes compensate — yet decompensate into heart failure after biomechanical stress, at least partly through cardiomyocyte apoptosis driven by telethonin's nuclear role in p53 turnover ("mechanoptosis"). Loss of telethonin mRNA with nuclear accumulation of the protein is also seen in human failing hearts. An independent Tcap-null line shows the same load-gated pattern in the excitation-contraction machinery: isolated t-tubule defects and desynchronised calcium transients at three months, progressive t-tubule loss by eight months, and accelerated t-tubule disruption specifically after aortic banding. This node is retained because it is the only in vivo mechanistic account of telethonin in the heart, but its direction of effect (loss of function) differs from the human HCM alleles (missense, gain of interaction), and the mouse phenotype is heart failure rather than hypertrophic cardiomyopathy.

Cardiomyocyte CL:0000746

Response to mechanical stimulus GO:0009612 ⚠ ABNORMAL Cardiac muscle cell apoptotic process GO:0010659 ↑ INCREASED T-tubule organization GO:0033292 ⚠ ABNORMAL

Downstream

Cardiomyocyte Hypertrophy

Show evidence (6 references)

PMID:21799151 SUPPORT Model Organism

"Telethonin knockout mice do not reveal defective heart development or heart function under basal conditions, but develop heart failure following biomechanical stress, owing at least in part to apoptosis of cardiomyocytes"

The core in vivo result: telethonin is dispensable at baseline but required for adaptation to biomechanical load, with apoptosis as the effector.

PMID:21799151 SUPPORT Model Organism

"We demonstrate that a main novel function of telethonin is to modulate the turnover of the proapoptotic tumor suppressor p53 after biomechanical stress in the nuclear compartment, thus linking telethonin, a protein well known to be present at the Z-disk, directly to apoptosis"

Identifies the molecular route (nuclear p53 turnover) from telethonin deficiency to stress-induced cardiomyocyte apoptosis.

PMID:21799151 SUPPORT Human Clinical

"In addition, loss of telethonin mRNA and nuclear accumulation of this protein is associated with human heart failure"

The one human observation linking telethonin dysregulation to myocardial disease. PARTIAL because it is an association in end-stage failing hearts of mixed aetiology, not in TCAP variant carriers.

+ 3 more references

Cardiomyocyte Hypertrophy

Whatever the upstream signalling route, the observed cellular phenotype in a TCAP variant carrier is the generic hypertrophic one. The single biopsy-documented case (a p.Glu12fs frameshift carrier) showed cardiomyocyte hypertrophy with focal fibrosis. There is no TCAP-specific cell or engineered-tissue model, so this node is supported by human histology rather than by mechanistic experiment.

Cardiomyocyte CL:0000746

Cardiac muscle hypertrophy GO:0003300 ↑ INCREASED

Downstream

Ventricular Remodeling with Sigmoidal Septal Geometry

Show evidence (1 reference)

PMID:40330574 SUPPORT Human Clinical

"Endomyocardial biopsy demonstrated cardiomyocyte hypertrophy and focal fibrosis."

The only tissue-level documentation of the cellular phenotype in a TCAP variant carrier with hypertrophic cardiomyopathy.

Ventricular Remodeling with Sigmoidal Septal Geometry

Cardiomyocyte hypertrophy plus interstitial matrix deposition remodels the left ventricle. The one distinguishing tissue-level observation for Z-disc HCM as a class — the group in which the single TCAP proband was counted — is the septal contour: Z-disc HCM was preferentially sigmoidal (85%) rather than reverse-curvature, the pattern typical of myofilament HCM. Whether this geometry holds for TCAP specifically cannot be determined from n=1.

Cardiomyocyte CL:0000746

Cardiac muscle hypertrophy GO:0003300 ↑ INCREASED Extracellular matrix organization GO:0030198 ↑ INCREASED

Heart left ventricle UBERON:0002084

Downstream

Left Ventricular Hypertrophy with Diastolic Dysfunction

Show evidence (2 references)

PMID:17097056 SUPPORT Human Clinical

"In contrast to myofilament-HCM, Z-disc-HCM is associated preferentially with sigmoidal morphology."

Distinguishes the remodeling geometry of Z-disc HCM from myofilament HCM. PARTIAL because the Z-disc group pooled LDB3, ACTN2, CSRP3, VCL, and a single TCAP proband, so the finding is class-level, not TCAP-specific.

PMID:17097056 SUPPORT Human Clinical

"For this subset with Z-disc-associated HCM, the septal contour was sigmoidal in 11 (85%) and apical in 2 (15%)."

Quantifies the septal-morphology distribution in Z-disc HCM. PARTIAL for the same class-level reason.

Left Ventricular Hypertrophy with Diastolic Dysfunction

The organ-level phenotype reported in TCAP variant carriers is left ventricular hypertrophy with impaired filling and a preserved ejection fraction — a diastolic, not a systolic, failure. Two independent reports converge on this: a Portuguese family with late-onset moderate asymmetric hypertrophy, atrial fibrillation, and heart failure with preserved ejection fraction, and a Chinese proband with non-obstructive hypertrophy, severe diastolic dysfunction, biatrial enlargement, preserved ejection fraction, and normal chamber size. Reported TCAP-HCM is clinically indistinguishable from myofilament HCM at the bedside.

Cardiac muscle hypertrophy GO:0003300 ↑ INCREASED Muscle contraction GO:0006936 ⚠ ABNORMAL

Heart left ventricle UBERON:0002084

Downstream

Progressive Heart Failure

Show evidence (3 references)

PMID:32565061 SUPPORT Human Clinical

"Both affected members of this family presented with late-onset HCM, moderate asymmetric left ventricular hypertrophy, atrial fibrillation and heart failure with preserved ejection fraction and low risk of sudden cardiac death."

Describes the organ-level phenotype in the only reported co-segregating TCAP HCM family.

PMID:40330574 SUPPORT Human Clinical

"Transthoracic echocardiography and cardiac magnetic resonance imaging (CMR) revealed non-obstructive hypertrophic cardiomyopathy (HCM) with severe diastolic dysfunction, biatrial enlargement, preserved ejection fraction, and normal chamber size."

Independent imaging confirmation of the diastolic, preserved-EF pattern in a second TCAP variant carrier.

PMID:16352453 SUPPORT Human Clinical

"Patients with MLP/TCAP-associated HCM clinically mimicked myofilament-HCM."

Establishes that the clinical presentation of TCAP-associated HCM is not distinguishable from sarcomeric HCM, which is why genotype rather than phenotype defines this entity.

Progressive Heart Failure

Outcome in the handful of reported carriers spans the full range. The Portuguese family had preserved-EF heart failure with an explicitly low estimated risk of sudden cardiac death, whereas the frameshift proband deteriorated over about a year despite treatment and was listed for cardiac transplantation. With this few patients no natural-history statement can be generalised.

Muscle contraction GO:0006936 ⚠ ABNORMAL

Show evidence (1 reference)

PMID:40330574 SUPPORT Human Clinical

"Despite interventions, the patient's cardiac function progressively deteriorated, leading to his placement on the heart transplant waiting list 1 year later."

Documents progression to advanced heart failure and transplant listing in a TCAP frameshift carrier.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

7

Cardiovascular 4

Hypertrophic Cardiomyopathy HP:0001639

Show evidence (2 references)

PMID:15582318 SUPPORT Human Clinical

"Two TCAP mutations, T137I and R153H, were found in patients with HCM"

The founding report of TCAP variants in hypertrophic cardiomyopathy probands.

PMID:32565061 SUPPORT Human Clinical

"We present a novel TCAP mutation in a small family affected by HCM. The identified p.C57W mutation showed a very low population frequency, as well as high conservation across species."

A further TCAP allele reported in a hypertrophic cardiomyopathy family after exclusion of eleven established HCM genes.

Left Ventricular Diastolic Dysfunction HP:0025168

Show evidence (1 reference)

PMID:40330574 SUPPORT Human Clinical

"severe diastolic dysfunction, biatrial enlargement, preserved ejection fraction, and normal chamber size"

Direct echocardiographic and CMR documentation of diastolic dysfunction.

Atrial Fibrillation HP:0005110

Show evidence (1 reference)

PMID:32565061 SUPPORT Human Clinical

"moderate asymmetric left ventricular hypertrophy, atrial fibrillation and heart failure with preserved ejection fraction"

Atrial fibrillation reported in both affected carriers of the TCAP p.C57W allele.

Congestive Heart Failure HP:0001635

Course: PROGRESSIVE

Show evidence (2 references)

PMID:32565061 SUPPORT Human Clinical

"heart failure with preserved ejection fraction and low risk of sudden cardiac death"

Heart failure with preserved ejection fraction in the TCAP p.C57W carriers.

PMID:40330574 SUPPORT Human Clinical

"A 47-year-old male presented with heart failure symptoms over a year, which had worsened in the past week."

Symptomatic, progressive heart failure as the presenting syndrome in a TCAP frameshift carrier.

Other 3

Asymmetric Septal Hypertrophy HP:0001670

Show evidence (2 references)

PMID:32565061 SUPPORT Human Clinical

"moderate asymmetric left ventricular hypertrophy"

Direct description of asymmetric hypertrophy in both affected TCAP p.C57W carriers.

PMID:17097056 SUPPORT Human Clinical

"In contrast to myofilament-HCM, Z-disc-HCM is associated preferentially with sigmoidal morphology."

Class-level septal-contour finding for Z-disc HCM. PARTIAL because only one of the 13 Z-disc probands carried a TCAP variant.

Restrictive Cardiomyopathy Physiology HP:0001723

n=1. The authors themselves state that the hypertrophic-restrictive mixed phenotype "ha[s] not yet been reported" for TCAP before their case.

Show evidence (1 reference)

PMID:40330574 SUPPORT Human Clinical

"The patient was diagnosed with hypertrophic cardiomyopathy with a restrictive phenotype (RP-HCM)."

Documents the restrictive physiology. PARTIAL because it is a single case report and the authors frame the TCAP contribution as "may contribute".

Myocardial Fibrosis HP:0001685

Show evidence (1 reference)

PMID:40330574 SUPPORT Human Clinical

"Endomyocardial biopsy demonstrated cardiomyocyte hypertrophy and focal fibrosis."

Histological documentation of myocardial fibrosis in a TCAP variant carrier.

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Genetic Associations

1

TCAP Variants Reported in Hypertrophic Cardiomyopathy (Reported Variants of Disputed Clinical Validity)

Gene: TCAP hgnc:11610 relationship_type: DISPUTED

Autosomal Dominant

Show evidence (6 references)

CGGV:assertion_c35abc20-c04c-49ec-af02-1bd270b0b50b-2022-09-14T160000.000Z SUPPORT Other

"has been DISPUTED. More evidence is needed to either support or entirely refute the role"

ClinGen's summary judgement on the TCAP-HCM gene-disease relationship, which is why `relationship_type` is DISPUTED rather than CAUSATIVE.

CGGV:assertion_c35abc20-c04c-49ec-af02-1bd270b0b50b-2022-09-14T160000.000Z SUPPORT Other

"As a result of this reevaluation, the classification changed from LIMITED to DISPUTED."

Records that the classification was actively downgraded in 2022 by the Hereditary Cardiovascular Disorders GCEP, not merely never upgraded.

CGGV:assertion_c35abc20-c04c-49ec-af02-1bd270b0b50b-2022-09-14T160000.000Z SUPPORT Other

"The TCAP gene was first associated with hypertrophic cardiomyopathy (HCM) in 2004 with missense variants found in 2 probands (Hayashi et al, PMID 15582318)."

ClinGen's enumeration of the primary case-level evidence base for the cardiac claim.

+ 3 more references

Variants (4)

TCAP T137I

Gene: TCAP hgnc:11610

Missense allele identified in a hypertrophic cardiomyopathy proband in the founding TCAP cardiomyopathy study; reported to augment telethonin binding to titin and calsarcin-1 in vitro.

TCAP R153H

Gene: TCAP hgnc:11610

Second missense allele found in a hypertrophic cardiomyopathy proband in the same study, with the same reported gain-of-interaction behaviour.

TCAP C57W

Gene: TCAP hgnc:11610

Missense allele reported in a small Portuguese HCM family after exclusion of eleven established HCM genes; very low population frequency, high cross-species conservation, in silico predictions of damage, and a co-segregation pattern within the family. No functional assay was performed.

TCAP p.Glu12fs

Gene: TCAP hgnc:11610

Heterozygous frameshift producing a truncated telethonin, identified by whole exome sequencing in a family with restrictive-phenotype hypertrophic cardiomyopathy. The first truncating allele reported in a hypertrophic presentation; the authors frame the contribution as possible rather than proven.

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Medical Actions

3

Genetic Counseling and Family Evaluation

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Counseling must convey that TCAP-HCM is a Disputed gene-disease relationship: a TCAP variant is not, on current evidence, a basis for predictive testing or for reassuring a variant-negative relative. Family evaluation should proceed on the standard nonsyndromic-HCM footing, driven by phenotype.

Show evidence (2 references)

PMID:20301725 SUPPORT Other

"Inform genetic counseling of family members of an individual with nonsyndromic HCM."

GeneReviews establishes family genetic counseling as a core component of nonsyndromic HCM care. Evidence source is OTHER because GeneReviews is an expert-authored review resource.

CGGV:assertion_c35abc20-c04c-49ec-af02-1bd270b0b50b-2022-09-14T160000.000Z SUPPORT Other

"has been DISPUTED. More evidence is needed to either support or entirely refute the role"

The validity statement that has to be communicated in counseling before a TCAP result is used for any family decision.

Anticoagulation for Atrial Fibrillation

Action: Pharmacotherapy NCIT:C15986

Agent: anticoagulant agent NCIT:C263

Atrial fibrillation is curated as a phenotype of this entity - it occurred in both affected carriers of the Portuguese p.C57W allele, and biatrial enlargement was present in the frameshift proband - and in hypertrophic cardiomyopathy its presence is itself the indication for anticoagulation, rather than being filtered through the risk scores used in atrial fibrillation without a cardiomyopathy substrate. It is recorded here because it is the management consequence of a phenotype this entry already asserts, and because applying the ordinary risk-score gate is a common and consequential error.

Target Phenotypes: Atrial fibrillation HP:0005110

Show evidence (1 reference)

PMID:32565061 SUPPORT Human Clinical

"moderate asymmetric left ventricular hypertrophy, atrial fibrillation and heart failure with preserved ejection fraction"

Documents the atrial fibrillation that constitutes the indication. PARTIAL because the source records the arrhythmia and does not report anticoagulation, its outcome, or any thromboembolic event in these carriers.

Heart Transplantation for End-Stage Disease

Action: heart transplantation Ontology label: Heart Transplantation NCIT:C15246

For the minority who progress to refractory heart failure despite guideline-directed therapy, transplantation is the endpoint of management, as in the reported frameshift carrier. There is no TCAP-directed therapy.

Show evidence (1 reference)

PMID:40330574 SUPPORT Human Clinical

"leading to his placement on the heart transplant waiting list 1 year later"

Transplant listing as the management endpoint in the one reported severe TCAP HCM case.

🔬

Diagnosis

5

Echocardiography

First-line imaging: establishes unexplained left ventricular hypertrophy, characterises its distribution (asymmetric/septal in the reported carriers), grades diastolic function, and documents atrial size. It is also the modality in which the sigmoidal septal contour of Z-disc HCM was defined.

echocardiography NCIT:C16525

Show evidence (2 references)

PMID:40330574 SUPPORT Human Clinical

"Transthoracic echocardiography and cardiac magnetic resonance imaging (CMR) revealed non-obstructive hypertrophic cardiomyopathy (HCM) with severe diastolic dysfunction"

Worked example of echocardiography establishing the phenotype in a TCAP carrier.

PMID:17097056 SUPPORT Human Clinical

"Blinded to the Z-disc genotype status, the septal contour was graded qualitatively using standard transthoracic echocardiography."

Documents transthoracic echocardiography as the method by which septal morphology is assessed in Z-disc HCM.

Cardiac Magnetic Resonance Imaging

CMR confirms the hypertrophy distribution, distinguishes non-obstructive from obstructive disease, and characterises the myocardium; in the reported frameshift carrier it was used alongside echocardiography to establish the restrictive-phenotype HCM diagnosis.

cardiac magnetic resonance imaging NCIT:C16809

Show evidence (1 reference)

PMID:40330574 SUPPORT Human Clinical

"Transthoracic echocardiography and cardiac magnetic resonance imaging (CMR) revealed non-obstructive hypertrophic cardiomyopathy (HCM) with severe diastolic dysfunction, biatrial enlargement, preserved ejection fraction, and normal chamber size."

CMR contribution to the diagnosis in the one detailed TCAP HCM case.

Endomyocardial Biopsy

Not routine in HCM, but in the single detailed TCAP case biopsy confirmed cardiomyocyte hypertrophy with focal fibrosis and helped exclude infiltrative causes of a restrictive physiology.

endomyocardial biopsy NCIT:C51674

Show evidence (1 reference)

PMID:40330574 SUPPORT Human Clinical

"Endomyocardial biopsy demonstrated cardiomyocyte hypertrophy and focal fibrosis."

Worked example of biopsy findings in a TCAP variant carrier with HCM.

Cardiomyopathy Multigene Panel or Exome Sequencing

Molecular testing is what defines this entity, because the clinical phenotype mirrors myofilament HCM. TCAP appears on legacy sarcomere/Z-disc panels and every reported cardiac allele was found by sequencing after the established genes were excluded. Critically, a TCAP variant returned by such a panel should NOT by itself be reported as a molecular diagnosis of HCM: ClinGen classifies the gene-disease relationship as Disputed, and the published variants lack functional support. Look actively for a second, better-supported variant — co-occurrence with a pathogenic TNNI3 variant and with a MYBPC3 VUS is documented in the TCAP HCM literature.

cardiomyopathy multigene panel or exome sequencing NCIT:C15709

Show evidence (4 references)

PMID:19035361 SUPPORT Human Clinical

"Index patients were screened for mutations in all coding regions of 10 sarcomere genes (MYH7, MYL3, MYBPC3, TNNI3, TNNT2, TPM1, ACTC, CSRP3, TCAP, and TNNC1) and five exons of TTN."

Documents TCAP's inclusion on the sarcomere/Z-disc gene panels used for HCM family screening.

PMID:32565061 SUPPORT Human Clinical

"After exclusion of mutations in eleven HCM disease genes, we performed direct sequencing of the TCAP gene encoding the Z-disk protein titin-cap (also known as telethonin)."

Shows the diagnostic position of TCAP: a candidate examined only after the established HCM genes are negative.

PMID:30681346 SUPPORT Human Clinical

"Classification of HCM genes and variants is critical, as misclassification can lead to genetic misdiagnosis."

The interpretive caveat that must accompany a TCAP result on an HCM panel, given the Disputed validity classification.

+ 1 more reference

Family Evaluation and Cascade Clinical Screening

Because a TCAP variant cannot carry a genetic diagnosis on its own, phenotype-based family evaluation retains primacy: clinical assessment with ECG and echocardiography in first-degree relatives, repeated over time. Danish HCM family-screening data show mutation status and clinical criteria disagree substantially in both directions, which is exactly the situation in a Disputed-gene family.

cascade clinical and electrocardiographic family screening NCIT:C38053

Show evidence (1 reference)

PMID:19035361 SUPPORT Human Clinical

"In relatives, 29.9% of mutation carriers did not fulfil any clinical diagnostic criterion, and in 37.5% of relatives without a mutation, one or more criteria was fulfilled."

Quantifies the genotype-phenotype discordance that makes ongoing clinical surveillance necessary alongside (not instead of) genetic testing.

📈

Progression

3

Genotype-positive, phenotype-negative relative

A relative found to carry a TCAP variant during cascade testing is in an unusually uncertain position, because the gene-disease relationship itself is Disputed: the variant may carry no risk at all. Danish HCM family data show that clinical criteria and mutation status disagree in both directions, so surveillance should be driven by family phenotype rather than by the TCAP result.

Show evidence (1 reference)

PMID:19035361 SUPPORT Human Clinical

"In relatives, 29.9% of mutation carriers did not fulfil any clinical diagnostic criterion"

Documents genotype-positive phenotype-negative status as a common state in HCM families. PARTIAL because the figure is panel-wide, not TCAP-specific.

Late-onset overt hypertrophic cardiomyopathy

In the only co-segregating family reported, both affected members declared late, with moderate asymmetric hypertrophy, atrial fibrillation, and preserved-EF heart failure, and were assessed as at low risk of sudden cardiac death.

Show evidence (1 reference)

PMID:32565061 SUPPORT Human Clinical

"Both affected members of this family presented with late-onset HCM, moderate asymmetric left ventricular hypertrophy, atrial fibrillation and heart failure with preserved ejection fraction and low risk of sudden cardiac death."

The only description of onset timing and risk profile in a TCAP HCM family.

Progression to advanced heart failure

At the severe end of the reported spectrum, a frameshift carrier with restrictive-phenotype HCM deteriorated over roughly a year despite treatment and was listed for transplantation. Whether this trajectory is TCAP-attributable or coincidental cannot be determined from one case.

Show evidence (1 reference)

PMID:40330574 SUPPORT Human Clinical

"Despite interventions, the patient's cardiac function progressively deteriorated, leading to his placement on the heart transplant waiting list 1 year later."

Documents the severe end of the reported outcome range.

📊

Prevalence

1

Worldwide

Unknown Not yet documented

No population prevalence estimate exists for the TCAP-attributed form of hypertrophic cardiomyopathy, and none can responsibly be derived while the gene-disease relationship is Disputed. The only quantitative anchors are yields in referral HCM cohorts: 4 of 389 unrelated HCM patients at a tertiary centre carried a TCAP variant (about 1%), and 1 of 239 myofilament-negative HCM patients carried a TCAP Z-disc variant. ClinGen notes that one of the Bos et al. variants (2 probands) is in fact common in the population, so even these low yields overstate the disease-attributable fraction.

Show evidence (3 references)

PMID:16352453 SUPPORT Human Clinical

"Overall, 16 patients (4.1%) harbored a Z-disc mutation: 12 had a MLP mutation and 4 patients a TCAP mutation."

Gives the TCAP yield (4 of 389 unrelated HCM probands) in a large tertiary referral cohort. PARTIAL because a clinic-cohort yield is not a population prevalence, and ClinGen subsequently judged one of these variants to be a common population variant.

PMID:17097056 SUPPORT Human Clinical

"Thirteen of the 239 patients (5.4%) had one of 13 distinct HCM-associated Z-disc mutations involving residues highly conserved across species and absent in 600 reference alleles: LDB3 (6), ACTN2 (3), TCAP (1), CSRP3 (1), and VCL (2)."

Places TCAP as a single-proband finding within the already-uncommon Z-disc HCM group in a myofilament-negative cohort. PARTIAL for the same reason: cohort yield, not population prevalence.

CGGV:assertion_c35abc20-c04c-49ec-af02-1bd270b0b50b-2022-09-14T160000.000Z SUPPORT Other

"Furthermore, 1 variant (2 probands) is common in the population (Bos et al, 2006, PMID 16352453), and 2 co-occurred with other variants"

ClinGen's re-analysis of the same cohort data shows the reported yields overstate the disease-attributable fraction, which is why no prevalence band is asserted.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Hypertrophic Cardiomyopathy 25:

Myofilament (sarcomeric) hypertrophic cardiomyopathy Not Yet Curated MONDO:0024573

Overlapping Features The definitive HCM genes — MYBPC3, MYH7, TNNT2, TNNI3, TPM1, ACTC1, MYL2, MYL3 — account for the overwhelming majority of genotyped HCM and are clinically indistinguishable from the reported TCAP cases. This is the primary differential and, given the Disputed status of TCAP, the more likely explanation whenever both are on the table.

Distinguishing Features

Only genotype separates them; MLP/TCAP-associated HCM clinically mimics myofilament HCM.
Septal contour differs at the class level (Z-disc HCM sigmoidal, myofilament HCM more often reverse-curvature), but this is a group tendency, not a patient-level discriminator.
A definitive-gene variant in the same patient should be regarded as the diagnosis; TCAP co-occurrence with a pathogenic TNNI3 variant is documented.

Show evidence (1 reference)

PMID:16352453 SUPPORT Human Clinical

"MLP/TCAP-HCM phenotypically mirrors myofilament-HCM and is more severe than the subset of patients who still remain without a disease"

Establishes that phenotype alone cannot separate TCAP-attributed HCM from sarcomeric HCM.

TCAP-related autosomal recessive limb-girdle muscular dystrophy (LGMD R7/2G) Not Yet Curated MONDO:0011170

Overlapping Features The best-evidenced TCAP disease is skeletal, not cardiac: ClinGen classifies TCAP-LGMD as Definitive, with biallelic loss of function as the expected mechanism. Most reported TCAP variants in the literature belong to this entity. It is listed here specifically as a named-entity-confusion guard: a TCAP paper or variant record is far more likely to be about LGMD R7 than about CMH25.

Distinguishing Features

Autosomal recessive with biallelic loss-of-function alleles, versus heterozygous (mostly missense) alleles in the cardiac reports.
Presents with progressive proximal muscle weakness in the second decade and raised creatine kinase, not with unexplained left ventricular hypertrophy.
ClinGen validity is Definitive for LGMD versus Disputed for hypertrophic cardiomyopathy.

Show evidence (2 references)

CGGV:assertion_f3c6c72e-7c2b-42d4-963b-aeddbbe0e4fc-2024-08-14T190000.000Z SUPPORT Other

ClinGen classifies the TCAP-LGMD relationship as Definitive with autosomal recessive inheritance, in contrast to the Disputed autosomal dominant cardiac claim.

CGGV:assertion_f3c6c72e-7c2b-42d4-963b-aeddbbe0e4fc-2024-08-14T190000.000Z SUPPORT Other

"The mechanism for disease is expected to be biallelic loss of function."

The mechanistic contrast that keeps the two entities separate: biallelic loss of function in LGMD versus monoallelic missense alleles reported in the cardiac literature.

{ }

Source YAML

click to show

name: Hypertrophic Cardiomyopathy 25
creation_date: "2026-08-01T00:00:00Z"
synonyms:
- CMH25
- TCAP hypertrophic cardiomyopathy
- cardiomyopathy, hypertrophic, 25
- cardiomyopathy, familial hypertrophic, type 25
- hypertrophic cardiomyopathy type 25
description: >-
  Hypertrophic cardiomyopathy 25 (CMH25) is the TCAP-attributed node of the
  hypertrophic cardiomyopathy gene series. TCAP encodes telethonin (titin-cap),
  a 19-kDa Z-disc protein that caps and cross-links the N-terminal (Z1Z2) region
  of two antiparallel titin molecules and nucleates a Z-disc signalosome
  including muscle LIM protein (MLP/CSRP3) and the calsarcins, the complex
  classically proposed to act as the cardiomyocyte biomechanical stretch sensor.
  The lesion is therefore framed at the Z-disc / mechanosensing level rather
  than as a thick- or thin-filament contractile defect: the reported
  HCM-associated missense changes do not abolish telethonin but alter its
  binding behaviour within that complex.

  The entity must be read with an explicit validity caveat. ClinGen's Hereditary
  Cardiovascular Disease Gene Curation Expert Panel classifies the TCAP-HCM
  gene-disease relationship as **Disputed** (downgraded from Limited in
  September 2022): the association rests on missense variants in roughly eight
  probands across four studies, none of the variants has functional evidence
  supporting pathogenicity, one variant is common in the population, two
  co-occurred with variants in other genes, and the disease mechanism is
  unknown. Dismech therefore curates CMH25 as a real MONDO entity whose
  pathophysiology is a *hypothesis under dispute*, not an established mechanism.

  Named-entity caution: TCAP is Definitively associated with autosomal recessive
  limb-girdle muscular dystrophy R7/2G and Limited for dilated cardiomyopathy.
  Every claim in this entry is anchored to a hypertrophic-cardiomyopathy source;
  skeletal-muscle and dilated-phenotype literature is used only where explicitly
  labelled as allelic-series or differential-diagnosis context.
category: Genetic
notes: >-
  MONDO:0011843 carries the OMIM:607487 xref and is unusually multi-parented: it
  is_a `familial hypertrophic cardiomyopathy` (MONDO:0024573), `familial dilated
  cardiomyopathy` (MONDO:0016333), AND `neuromuscular disease caused by
  qualitative or quantitative defects of telethonin` (MONDO:0016192). That triple
  parentage is a direct encoding of the named-entity hazard around this gene: the
  TCAP literature mixes hypertrophic, dilated, and skeletal-muscle (LGMD R7/2G)
  phenotypes, and the gene aliases include both CMD1N and LGMD2G. This entry
  curates the hypertrophic arm only; the dilated and limb-girdle arms are
  represented here solely as differential diagnoses with their own ClinGen
  classifications. None of the three parent terms is currently curated in dismech
  (checked against origin/main at the time of creation).
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
disease_term:
  preferred_term: hypertrophic cardiomyopathy 25
  term:
    id: MONDO:0011843
    label: hypertrophic cardiomyopathy 25
parents:
- Hypertrophic Cardiomyopathy
- Genetic Disorder
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    No population prevalence estimate exists for the TCAP-attributed form of
    hypertrophic cardiomyopathy, and none can responsibly be derived while the
    gene-disease relationship is Disputed. The only quantitative anchors are
    yields in referral HCM cohorts: 4 of 389 unrelated HCM patients at a
    tertiary centre carried a TCAP variant (about 1%), and 1 of 239
    myofilament-negative HCM patients carried a TCAP Z-disc variant. ClinGen
    notes that one of the Bos et al. variants (2 probands) is in fact common in
    the population, so even these low yields overstate the disease-attributable
    fraction.
  evidence:
  - reference: PMID:16352453
    reference_title: Genotype-phenotype relationships involving hypertrophic cardiomyopathy-associated mutations in titin, muscle LIM protein, and telethonin.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Overall, 16 patients (4.1%) harbored a Z-disc mutation: 12 had a MLP
      mutation and 4 patients a TCAP mutation.
    explanation: >-
      Gives the TCAP yield (4 of 389 unrelated HCM probands) in a large tertiary
      referral cohort. PARTIAL because a clinic-cohort yield is not a population
      prevalence, and ClinGen subsequently judged one of these variants to be a
      common population variant.
  - reference: PMID:17097056
    reference_title: Echocardiographic-determined septal morphology in Z-disc hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thirteen of the 239 patients (5.4%) had one of 13 distinct HCM-associated
      Z-disc mutations involving residues highly conserved across species and
      absent in 600 reference alleles: LDB3 (6), ACTN2 (3), TCAP (1), CSRP3 (1),
      and VCL (2).
    explanation: >-
      Places TCAP as a single-proband finding within the already-uncommon Z-disc
      HCM group in a myofilament-negative cohort. PARTIAL for the same reason:
      cohort yield, not population prevalence.
  - reference: CGGV:assertion_c35abc20-c04c-49ec-af02-1bd270b0b50b-2022-09-14T160000.000Z
    reference_title: "TCAP / hypertrophic cardiomyopathy (Disputed)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Furthermore, 1 variant (2 probands) is common in the population (Bos et
      al, 2006, PMID 16352453), and 2 co-occurred with other variants
    explanation: >-
      ClinGen's re-analysis of the same cohort data shows the reported yields
      overstate the disease-attributable fraction, which is why no prevalence
      band is asserted.
inheritance:
- name: Autosomal Dominant
  description: >-
    Where a mode of inheritance has been recorded for TCAP cardiomyopathy it is
    autosomal dominant heterozygous transmission of a missense (or, in one
    report, frameshift) allele. Segregation data are thin: a single small
    Portuguese family demonstrated co-segregation of the p.C57W allele, and the
    2025 frameshift report identified the variant in the proband's family.
    Contrast with the TCAP skeletal-muscle disease (LGMD R7/2G), which is
    autosomal recessive and biallelic loss of function.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: CGGV:assertion_c35abc20-c04c-49ec-af02-1bd270b0b50b-2022-09-14T160000.000Z
    reference_title: "TCAP / hypertrophic cardiomyopathy (Disputed)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      TCAP | HGNC:11610 | hypertrophic cardiomyopathy | MONDO:0005045 | AD |
      Disputed
    explanation: >-
      ClinGen records autosomal dominant inheritance for the TCAP-HCM
      gene-disease relationship, alongside the Disputed validity classification.
  - reference: PMID:32565061
    reference_title: Identification of a novel titin-cap/telethonin mutation in a Portuguese family with hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Family members were screened for this new mutation and a co-segregation
      pattern was detected.
    explanation: >-
      The only published co-segregation observation for a TCAP HCM allele.
      PARTIAL because the family is explicitly described as small, so the
      segregation evidence is weak on its own.
mechanistic_hypotheses:
- hypothesis_group_id: tcap_zdisc_stretch_sensor_gain_of_interaction
  hypothesis_label: Z-disc stretch-sensor gain-of-interaction model
  status: EMERGING
  description: >-
    The only mechanistic model proposed for TCAP-HCM holds that the
    hypertrophic and dilated phenotypes are separated by the *direction* of the
    binding change within the titin/telethonin/MLP Z-disc stretch sensor: the
    two HCM-associated missense alleles (T137I, R153H) augmented telethonin's
    interaction with titin and calsarcin-1 in yeast two-hybrid and GST
    pull-down assays, whereas the DCM-associated alleles impaired binding to
    MLP, titin, and calsarcin-1. Because calsarcin tethers calcineurin — a
    canonical pro-hypertrophic phosphatase — to the Z-disc, a gain of
    telethonin-calsarcin interaction is the proposed route from a Z-disc
    scaffolding change to hypertrophic growth. This remains EMERGING and
    contested: the assays were qualitative, no downstream calcineurin readout
    was measured in the original work, no independent group has replicated the
    binding result, and ClinGen states outright that the disease mechanism is
    unknown.
  evidence:
  - reference: PMID:15582318
    reference_title: Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      It was demonstrated by the qualitative assays that the HCM-associated
      mutations augment the ability of Tcap to interact with titin and
      calsarcin-1, whereas the DCM-associated mutations impair the interaction
      of Tcap with MLP, titin, and calsarcin-1.
    explanation: >-
      The primary in vitro basis for the gain-of-interaction model and for the
      HCM-versus-DCM directional split. Evidence source is IN_VITRO because the
      result comes from yeast two-hybrid and GST pull-down competition assays.
  - reference: PMID:15582318
    reference_title: Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      These observations suggest that the difference in clinical phenotype (HCM
      or DCM) may be correlated with the property of altered binding among the
      Z-disc components.
    explanation: >-
      The authors state the hypothesis in their own hedged terms ("may be
      correlated"), which is why this group is EMERGING rather than CANONICAL.
      Evidence source is OTHER because the quote is the paper's interpretive
      conclusion rather than a measurement.
  - reference: CGGV:assertion_c35abc20-c04c-49ec-af02-1bd270b0b50b-2022-09-14T160000.000Z
    reference_title: "TCAP / hypertrophic cardiomyopathy (Disputed)"
    supports: REFUTE
    evidence_source: OTHER
    snippet: "The mechanism for disease is unknown."
    explanation: >-
      ClinGen's expert-panel judgement that no disease mechanism is established
      for TCAP-HCM. Recorded as REFUTE against the claim that this model is
      settled; it is the reason the hypothesis is not marked CANONICAL.
pathophysiology:
- name: Telethonin Z-Disc Titin-Capping and Stretch-Sensor Perturbation
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  biological_scale: MOLECULAR
  role: trigger
  mechanism_confidence: HYPOTHETICAL
  description: >-
    TCAP encodes telethonin, a small Z-disc protein that assembles with the
    N-terminal immunoglobulin domains of two antiparallel titin molecules,
    capping the Z-disc end of titin and nucleating a signalosome that also
    contains muscle LIM protein (MLP/CSRP3), the calsarcins, and — as more
    recently shown — nesprin-2 and FHL-2. This complex, not the contractile
    filaments, is the proposed proximal lesion: the HCM-associated alleles
    reported to date (T137I, R153H, C57W, and one p.Glu12fs frameshift) change
    how telethonin engages its Z-disc partners rather than removing the protein
    from the sarcomere. The trigger is deliberately tagged HYPOTHETICAL: no
    functional assay has established pathogenicity for any of these alleles.
  genes:
  - preferred_term: TCAP
    term:
      id: hgnc:11610
      label: TCAP
  cellular_components:
  - preferred_term: Z disc
    term:
      id: GO:0030018
      label: Z disc
  molecular_functions:
  - preferred_term: titin binding
    term:
      id: GO:0031432
      label: titin 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
  biological_processes:
  - preferred_term: Detection of muscle stretch
    term:
      id: GO:0035995
      label: detection of muscle stretch
    modifier: ABNORMAL
  evidence:
  - reference: PMID:15582318
    reference_title: Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The Z-disc plays a role in establishing the mechanical coupling of
      sarcomeric contraction and stretching, with the titin/Tcap/MLP complex
      serving as a mechanical stretch sensor.
    explanation: >-
      States the normal Z-disc stretch-sensor role of the titin/telethonin/MLP
      complex whose perturbation is the proposed primary lesion. Evidence source
      is OTHER because the quote is the paper's background framing.
  - reference: PMID:16352453
    reference_title: Genotype-phenotype relationships involving hypertrophic cardiomyopathy-associated mutations in titin, muscle LIM protein, and telethonin.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      TTN-encoded titin, CSRP3-encoded muscle LIM protein, and TCAP-encoded
      telethonin are Z-disc proteins essential for the structural organization
      of the cardiac sarcomere and the cardiomyocyte's stretch sensor.
    explanation: >-
      Independent statement, from the HCM cohort study itself, that telethonin
      belongs to the Z-disc structural and stretch-sensing apparatus rather than
      the myofilament. Evidence source is OTHER because it is background framing.
  - reference: PMID:21799151
    reference_title: Telethonin deficiency is associated with maladaptation to biomechanical stress in the mammalian heart.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      hypothesized to assemble in a palindromic way with the N-terminal portion
      of titin and to constitute a signalosome participating in the process of
      cardiomechanosensing
    explanation: >-
      Supplies the structural detail of the titin-capping arrangement and the
      signalosome framing. Evidence source is OTHER because the quote is the
      study's stated rationale rather than its result.
  - reference: PMID:15582318
    reference_title: Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two TCAP mutations, T137I and R153H, were found in patients with HCM, and
      another TCAP mutation, E132Q, was identified in a patient with DCM.
    explanation: >-
      The founding CMH25 observation: two TCAP missense alleles in hypertrophic
      cardiomyopathy probands, distinct from the dilated-phenotype allele in the
      same study.
  - reference: PMID:38569934
    reference_title: Nesprin-2 is a novel scaffold protein for telethonin and FHL-2 in the cardiomyocyte sarcomere.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Importantly, the interactions between these binding partners were impaired
      by mutations in nesprin-2, telethonin, and FHL-2 identified in EDMD with
      DCM and hypertrophic cardiomyopathy patients.
    explanation: >-
      Extends the telethonin Z-disc interactome to nesprin-2 and FHL-2 and shows
      that cardiomyopathy-associated mutations disturb those interactions.
      PARTIAL because the tested mutation set spans EDMD/DCM as well as HCM, so
      the result is not specific to the CMH25 alleles.
  - reference: CGGV:assertion_c35abc20-c04c-49ec-af02-1bd270b0b50b-2022-09-14T160000.000Z
    reference_title: "TCAP / hypertrophic cardiomyopathy (Disputed)"
    supports: REFUTE
    evidence_source: OTHER
    snippet: "None of these variants have functional evidence in support of pathogenicity."
    explanation: >-
      ClinGen's finding that the reported TCAP HCM alleles lack supporting
      functional data. This is why the trigger node carries
      `mechanism_confidence: HYPOTHETICAL` rather than being asserted as
      established.
  - reference: PMID:12507422
    reference_title: The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "MLP interacts with and colocalizes with telethonin (T-cap), a titin interacting protein."
    explanation: >-
      The canonical demonstration that telethonin partners with muscle LIM
      protein in the Z-disc stretch-sensor complex. PARTIAL, and deliberately
      flagged: this study's disease framing is dilated cardiomyopathy, not
      hypertrophic. It is included because ClinGen counts precisely this
      telethonin-CSRP3 interaction among the non-genetic experimental evidence
      it weighed for the TCAP-HCM relationship.
  - reference: CGGV:assertion_c35abc20-c04c-49ec-af02-1bd270b0b50b-2022-09-14T160000.000Z
    reference_title: "TCAP / hypertrophic cardiomyopathy (Disputed)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      and an interaction with CSRP3 (Knoll et al. 2002, PMID 12507422; Vafiadaki
      et al. 2014, PMID 24860983) which has moderate evidence for HCM
    explanation: >-
      Records that the only experimental support ClinGen credited for the
      TCAP-HCM relationship is expression data plus the telethonin-CSRP3
      interaction — guilt by association with a moderate-evidence HCM gene, not
      direct evidence about TCAP alleles.
  downstream:
  - target: Altered Z-Disc Signalosome Output
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - tcap_zdisc_stretch_sensor_gain_of_interaction
    description: >-
      Proposed, not demonstrated: the causal step from altered telethonin
      binding to a changed hypertrophic signalling output has never been
      measured in cardiomyocytes carrying an HCM allele.
  - target: Impaired Myocardial Adaptation to Biomechanical Stress
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Supported only by loss-of-function model organisms, whose relevance to the
      human missense alleles is unresolved (see the HUMAN_MODEL_MISMATCH
      discussion).

- name: Altered Z-Disc Signalosome Output
  biological_scale: CELLULAR
  role: amplifier
  mechanism_confidence: HYPOTHETICAL
  description: >-
    The proposed intracellular consequence of a mis-binding telethonin is a
    change in the signalling output of the Z-disc, not a change in force
    production. Telethonin binds calsarcin, and calsarcin tethers the
    pro-hypertrophic phosphatase calcineurin to the Z-disc; the two
    HCM-associated alleles increased telethonin's affinity for titin and
    calsarcin-1 in vitro, which is the proposed route to a hypertrophic
    transcriptional program. No calcineurin, NFAT, or hypertrophy readout has
    been measured in any TCAP-HCM model, so this node is a mechanistic
    placeholder held together by protein-interaction data alone.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  cellular_components:
  - preferred_term: Z disc
    term:
      id: GO:0030018
      label: Z disc
  biological_processes:
  - preferred_term: Detection of muscle stretch
    term:
      id: GO:0035995
      label: detection of muscle stretch
    modifier: ABNORMAL
  - preferred_term: Response to mechanical stimulus
    term:
      id: GO:0009612
      label: response to mechanical stimulus
    modifier: ABNORMAL
  evidence:
  - reference: PMID:15582318
    reference_title: Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Tcap interacts with the calsarcin, which tethers the calcineurin to the Z-disc."
    explanation: >-
      Establishes the telethonin-calsarcin-calcineurin tether that makes a
      hypertrophic signalling output mechanistically plausible. Evidence source
      is OTHER because the statement is background, not a result of this study.
  - reference: PMID:15582318
    reference_title: Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the HCM-associated mutations augment the ability of Tcap to interact with
      titin and calsarcin-1
    explanation: >-
      The measured binding change that the signalling hypothesis rests on.
      PARTIAL because increased calsarcin binding was not followed through to
      any calcineurin or hypertrophy readout.
  downstream:
  - target: Cardiomyocyte Hypertrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - tcap_zdisc_stretch_sensor_gain_of_interaction

- name: Impaired Myocardial Adaptation to Biomechanical Stress
  biological_scale: CELLULAR
  role: amplifier
  mechanism_confidence: HYPOTHETICAL
  description: >-
    The best-characterised in vivo consequence of losing telethonin is not a
    structural Z-disc collapse but a failure of stress adaptation. Telethonin
    knockout mice have normal hearts at baseline — other titin anchorage routes
    compensate — yet decompensate into heart failure after biomechanical stress,
    at least partly through cardiomyocyte apoptosis driven by telethonin's
    nuclear role in p53 turnover ("mechanoptosis"). Loss of telethonin mRNA with
    nuclear accumulation of the protein is also seen in human failing hearts. An
    independent Tcap-null line shows the same load-gated pattern in the
    excitation-contraction machinery: isolated t-tubule defects and desynchronised
    calcium transients at three months, progressive t-tubule loss by eight months,
    and accelerated t-tubule disruption specifically after aortic banding. This
    node is retained because it is the only in vivo mechanistic account of
    telethonin in the heart, but its direction of effect (loss of function)
    differs from the human HCM alleles (missense, gain of interaction), and the
    mouse phenotype is heart failure rather than hypertrophic cardiomyopathy.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Response to mechanical stimulus
    term:
      id: GO:0009612
      label: response to mechanical stimulus
    modifier: ABNORMAL
  - preferred_term: Cardiac muscle cell apoptotic process
    term:
      id: GO:0010659
      label: cardiac muscle cell apoptotic process
    modifier: INCREASED
  - preferred_term: T-tubule organization
    term:
      id: GO:0033292
      label: T-tubule organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:21799151
    reference_title: Telethonin deficiency is associated with maladaptation to biomechanical stress in the mammalian heart.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Telethonin knockout mice do not reveal defective heart development or
      heart function under basal conditions, but develop heart failure following
      biomechanical stress, owing at least in part to apoptosis of
      cardiomyocytes
    explanation: >-
      The core in vivo result: telethonin is dispensable at baseline but
      required for adaptation to biomechanical load, with apoptosis as the
      effector.
  - reference: PMID:21799151
    reference_title: Telethonin deficiency is associated with maladaptation to biomechanical stress in the mammalian heart.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We demonstrate that a main novel function of telethonin is to modulate the
      turnover of the proapoptotic tumor suppressor p53 after biomechanical
      stress in the nuclear compartment, thus linking telethonin, a protein well
      known to be present at the Z-disk, directly to apoptosis
    explanation: >-
      Identifies the molecular route (nuclear p53 turnover) from telethonin
      deficiency to stress-induced cardiomyocyte apoptosis.
  - reference: PMID:21799151
    reference_title: Telethonin deficiency is associated with maladaptation to biomechanical stress in the mammalian heart.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, loss of telethonin mRNA and nuclear accumulation of this
      protein is associated with human heart failure
    explanation: >-
      The one human observation linking telethonin dysregulation to myocardial
      disease. PARTIAL because it is an association in end-stage failing hearts
      of mixed aetiology, not in TCAP variant carriers.
  - reference: PMID:21799151
    reference_title: Telethonin deficiency is associated with maladaptation to biomechanical stress in the mammalian heart.
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we show that contrary to previous views, telethonin is not an indispensable
      component of the titin-anchoring system, nor is deletion of the gene or
      cardiac specific overexpression associated with a spontaneous cardiac
      phenotype.
    explanation: >-
      Directly refutes a simple structural loss-of-anchorage account of TCAP
      cardiomyopathy, and refutes the idea that telethonin dosage alone produces
      a spontaneous cardiac phenotype.
  - reference: PMID:23100327
    reference_title: A critical role for Telethonin in regulating t-tubule structure and function in the mammalian heart.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Mechanical overload increased the Ca(2+) spark frequency in KO alone, where
      there was also significantly more t-tubule loss, with a greater
      deterioration in t-tubule regularity.
    explanation: >-
      Independent Tcap-null evidence that the deficit is load-gated: the t-tubule
      and calcium-handling phenotype is unmasked by mechanical overload, matching
      the maladaptation-to-stress framing of this node.
  - reference: PMID:23100327
    reference_title: A critical role for Telethonin in regulating t-tubule structure and function in the mammalian heart.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These data suggest that Tcap is a critical, load-sensitive regulator of t-tubule structure and function."
    explanation: >-
      The authors' summary of telethonin's load-sensing role in maintaining
      t-tubule structure, the excitation-contraction correlate of the
      mechanosensing defect.
  downstream:
  - target: Cardiomyocyte Hypertrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES

- name: Cardiomyocyte Hypertrophy
  biological_scale: CELLULAR
  role: effector
  mechanism_confidence: PROVISIONAL
  description: >-
    Whatever the upstream signalling route, the observed cellular phenotype in a
    TCAP variant carrier is the generic hypertrophic one. The single
    biopsy-documented case (a p.Glu12fs frameshift carrier) showed cardiomyocyte
    hypertrophy with focal fibrosis. There is no TCAP-specific cell or
    engineered-tissue model, so this node is supported by human histology rather
    than by mechanistic experiment.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Cardiac muscle hypertrophy
    term:
      id: GO:0003300
      label: cardiac muscle hypertrophy
    modifier: INCREASED
  notes: >-
    This node was narrowed during review. It previously read "Sarcomeric Z-Disc
    Disorganization and Cardiomyocyte Hypertrophy" and carried GO:0045214
    sarcomere organization (ABNORMAL) alongside the hypertrophy term. The single
    evidence item available - the endomyocardial biopsy in the one reported case
    - documents cardiomyocyte hypertrophy and focal fibrosis and says nothing
    about sarcomere or Z-disc architecture, and no other cached source for this
    entity reports disarray or myofibrillar disorganization either. The node was
    therefore narrowed to the claim the evidence supports, and the GO:0045214
    annotation dropped, rather than split into a second node that would have had
    no evidence to stand on. Z-disc disorganization is a plausible expectation
    for a Z-disc protein, but plausibility is exactly what this DISPUTED entity
    must not encode as observation. If a TCAP biopsy or model reporting
    myofibrillar architecture appears, a separate sourced node is the right way
    to add it.
  evidence:
  - reference: PMID:40330574
    reference_title: "Mutations in the TCAP gene may lead to restrictive phenotype hypertrophic cardiomyopathy with poor prognosis: case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Endomyocardial biopsy demonstrated cardiomyocyte hypertrophy and focal fibrosis."
    explanation: >-
      The only tissue-level documentation of the cellular phenotype in a TCAP
      variant carrier with hypertrophic cardiomyopathy.
  downstream:
  - target: Ventricular Remodeling with Sigmoidal Septal Geometry
    causal_link_type: DIRECT

- name: Ventricular Remodeling with Sigmoidal Septal Geometry
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
  biological_scale: TISSUE
  role: central_effector
  mechanism_confidence: PROVISIONAL
  description: >-
    Cardiomyocyte hypertrophy plus interstitial matrix deposition remodels the
    left ventricle. The one distinguishing tissue-level observation for Z-disc
    HCM as a class — the group in which the single TCAP proband was counted — is
    the septal contour: Z-disc HCM was preferentially sigmoidal (85%) rather
    than reverse-curvature, the pattern typical of myofilament HCM. Whether this
    geometry holds for TCAP specifically cannot be determined from n=1.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: Heart left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  biological_processes:
  - preferred_term: Cardiac muscle hypertrophy
    term:
      id: GO:0003300
      label: cardiac muscle hypertrophy
    modifier: INCREASED
  - preferred_term: Extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  evidence:
  - reference: PMID:17097056
    reference_title: Echocardiographic-determined septal morphology in Z-disc hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast to myofilament-HCM, Z-disc-HCM is associated preferentially
      with sigmoidal morphology.
    explanation: >-
      Distinguishes the remodeling geometry of Z-disc HCM from myofilament HCM.
      PARTIAL because the Z-disc group pooled LDB3, ACTN2, CSRP3, VCL, and a
      single TCAP proband, so the finding is class-level, not TCAP-specific.
  - reference: PMID:17097056
    reference_title: Echocardiographic-determined septal morphology in Z-disc hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      For this subset with Z-disc-associated HCM, the septal contour was
      sigmoidal in 11 (85%) and apical in 2 (15%).
    explanation: >-
      Quantifies the septal-morphology distribution in Z-disc HCM. PARTIAL for
      the same class-level reason.
  downstream:
  - target: Left Ventricular Hypertrophy with Diastolic Dysfunction
    causal_link_type: DIRECT

- name: Left Ventricular Hypertrophy with Diastolic Dysfunction
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Progressive Contractile Dysfunction"
  biological_scale: ORGANISM
  role: effector
  mechanism_confidence: PROVISIONAL
  description: >-
    The organ-level phenotype reported in TCAP variant carriers is left
    ventricular hypertrophy with impaired filling and a preserved ejection
    fraction — a diastolic, not a systolic, failure. Two independent reports
    converge on this: a Portuguese family with late-onset moderate asymmetric
    hypertrophy, atrial fibrillation, and heart failure with preserved ejection
    fraction, and a Chinese proband with non-obstructive hypertrophy, severe
    diastolic dysfunction, biatrial enlargement, preserved ejection fraction,
    and normal chamber size. Reported TCAP-HCM is clinically indistinguishable
    from myofilament HCM at the bedside.
  locations:
  - preferred_term: Heart left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  biological_processes:
  - preferred_term: Cardiac muscle hypertrophy
    term:
      id: GO:0003300
      label: cardiac muscle hypertrophy
    modifier: INCREASED
  - preferred_term: Muscle contraction
    term:
      id: GO:0006936
      label: muscle contraction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:32565061
    reference_title: Identification of a novel titin-cap/telethonin mutation in a Portuguese family with hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both affected members of this family presented with late-onset HCM,
      moderate asymmetric left ventricular hypertrophy, atrial fibrillation and
      heart failure with preserved ejection fraction and low risk of sudden
      cardiac death.
    explanation: >-
      Describes the organ-level phenotype in the only reported co-segregating
      TCAP HCM family.
  - reference: PMID:40330574
    reference_title: "Mutations in the TCAP gene may lead to restrictive phenotype hypertrophic cardiomyopathy with poor prognosis: case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Transthoracic echocardiography and cardiac magnetic resonance imaging
      (CMR) revealed non-obstructive hypertrophic cardiomyopathy (HCM) with
      severe diastolic dysfunction, biatrial enlargement, preserved ejection
      fraction, and normal chamber size.
    explanation: >-
      Independent imaging confirmation of the diastolic, preserved-EF pattern in
      a second TCAP variant carrier.
  - reference: PMID:16352453
    reference_title: Genotype-phenotype relationships involving hypertrophic cardiomyopathy-associated mutations in titin, muscle LIM protein, and telethonin.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with MLP/TCAP-associated HCM clinically mimicked myofilament-HCM."
    explanation: >-
      Establishes that the clinical presentation of TCAP-associated HCM is not
      distinguishable from sarcomeric HCM, which is why genotype rather than
      phenotype defines this entity.
  downstream:
  - target: Progressive Heart Failure
    causal_link_type: DIRECT

- name: Progressive Heart Failure
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure"
  biological_scale: ORGANISM
  role: consequence
  mechanism_confidence: PROVISIONAL
  description: >-
    Outcome in the handful of reported carriers spans the full range. The
    Portuguese family had preserved-EF heart failure with an explicitly low
    estimated risk of sudden cardiac death, whereas the frameshift proband
    deteriorated over about a year despite treatment and was listed for cardiac
    transplantation. With this few patients no natural-history statement can be
    generalised.
  biological_processes:
  - preferred_term: Muscle contraction
    term:
      id: GO:0006936
      label: muscle contraction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:40330574
    reference_title: "Mutations in the TCAP gene may lead to restrictive phenotype hypertrophic cardiomyopathy with poor prognosis: case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Despite interventions, the patient's cardiac function progressively
      deteriorated, leading to his placement on the heart transplant waiting
      list 1 year later.
    explanation: >-
      Documents progression to advanced heart failure and transplant listing in
      a TCAP frameshift carrier.
phenotypes:
- category: Cardiovascular
  name: Hypertrophic Cardiomyopathy
  description: >-
    Unexplained left ventricular hypertrophy is the defining feature of the
    entity. It has been reported in probands carrying TCAP missense alleles in
    Japanese/Korean, US tertiary-referral, Danish, and Portuguese cohorts, and
    in one frameshift carrier.
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  evidence:
  - reference: PMID:15582318
    reference_title: Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two TCAP mutations, T137I and R153H, were found in patients with HCM"
    explanation: The founding report of TCAP variants in hypertrophic cardiomyopathy probands.
  - reference: PMID:32565061
    reference_title: Identification of a novel titin-cap/telethonin mutation in a Portuguese family with hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We present a novel TCAP mutation in a small family affected by HCM. The
      identified p.C57W mutation showed a very low population frequency, as well
      as high conservation across species.
    explanation: >-
      A further TCAP allele reported in a hypertrophic cardiomyopathy family
      after exclusion of eleven established HCM genes.
- category: Cardiovascular
  name: Asymmetric Septal Hypertrophy
  description: >-
    Where hypertrophy distribution has been described in TCAP carriers it is
    asymmetric and septal; at the class level, Z-disc HCM is preferentially
    sigmoidal rather than reverse-curvature in septal contour.
  phenotype_term:
    preferred_term: Asymmetric septal hypertrophy
    term:
      id: HP:0001670
      label: Asymmetric septal hypertrophy
  evidence:
  - reference: PMID:32565061
    reference_title: Identification of a novel titin-cap/telethonin mutation in a Portuguese family with hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "moderate asymmetric left ventricular hypertrophy"
    explanation: Direct description of asymmetric hypertrophy in both affected TCAP p.C57W carriers.
  - reference: PMID:17097056
    reference_title: Echocardiographic-determined septal morphology in Z-disc hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast to myofilament-HCM, Z-disc-HCM is associated preferentially
      with sigmoidal morphology.
    explanation: >-
      Class-level septal-contour finding for Z-disc HCM. PARTIAL because only
      one of the 13 Z-disc probands carried a TCAP variant.
- category: Cardiovascular
  name: Left Ventricular Diastolic Dysfunction
  description: >-
    Impaired ventricular filling with a preserved ejection fraction is the
    functional signature in the reported carriers, in one case severe enough to
    produce a restrictive physiology.
  phenotype_term:
    preferred_term: Left ventricular diastolic dysfunction
    term:
      id: HP:0025168
      label: Left ventricular diastolic dysfunction
  evidence:
  - reference: PMID:40330574
    reference_title: "Mutations in the TCAP gene may lead to restrictive phenotype hypertrophic cardiomyopathy with poor prognosis: case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      severe diastolic dysfunction, biatrial enlargement, preserved ejection
      fraction, and normal chamber size
    explanation: Direct echocardiographic and CMR documentation of diastolic dysfunction.
- category: Cardiovascular
  name: Restrictive Cardiomyopathy Physiology
  description: >-
    One proband with a heterozygous TCAP frameshift allele presented with a
    mixed hypertrophic-restrictive picture (restrictive-phenotype HCM), with a
    mother diagnosed with restrictive cardiomyopathy. This is a single report
    and should be read as a described presentation, not an established feature.
  phenotype_term:
    preferred_term: Restrictive cardiomyopathy
    term:
      id: HP:0001723
      label: Restrictive cardiomyopathy
  notes: >-
    n=1. The authors themselves state that the hypertrophic-restrictive mixed
    phenotype "ha[s] not yet been reported" for TCAP before their case.
  evidence:
  - reference: PMID:40330574
    reference_title: "Mutations in the TCAP gene may lead to restrictive phenotype hypertrophic cardiomyopathy with poor prognosis: case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient was diagnosed with hypertrophic cardiomyopathy with a restrictive phenotype (RP-HCM)."
    explanation: >-
      Documents the restrictive physiology. PARTIAL because it is a single case
      report and the authors frame the TCAP contribution as "may contribute".
- category: Cardiovascular
  name: Atrial Fibrillation
  description: >-
    Atrial fibrillation occurred in the affected members of the Portuguese TCAP
    p.C57W family; biatrial enlargement was present in the frameshift proband.
  phenotype_term:
    preferred_term: Atrial fibrillation
    term:
      id: HP:0005110
      label: Atrial fibrillation
  evidence:
  - reference: PMID:32565061
    reference_title: Identification of a novel titin-cap/telethonin mutation in a Portuguese family with hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "moderate asymmetric left ventricular hypertrophy, atrial fibrillation and heart failure with preserved ejection fraction"
    explanation: Atrial fibrillation reported in both affected carriers of the TCAP p.C57W allele.
- category: Cardiovascular
  name: Congestive Heart Failure
  description: >-
    Heart failure — with preserved ejection fraction in the Portuguese family,
    and progressing to transplant listing in the frameshift proband — is the
    principal clinical burden reported.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:32565061
    reference_title: Identification of a novel titin-cap/telethonin mutation in a Portuguese family with hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "heart failure with preserved ejection fraction and low risk of sudden cardiac death"
    explanation: Heart failure with preserved ejection fraction in the TCAP p.C57W carriers.
  - reference: PMID:40330574
    reference_title: "Mutations in the TCAP gene may lead to restrictive phenotype hypertrophic cardiomyopathy with poor prognosis: case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 47-year-old male presented with heart failure symptoms over a year, which had worsened in the past week."
    explanation: Symptomatic, progressive heart failure as the presenting syndrome in a TCAP frameshift carrier.
- category: Cardiovascular
  name: Myocardial Fibrosis
  description: >-
    Focal interstitial fibrosis was demonstrated on endomyocardial biopsy in the
    single biopsied TCAP carrier.
  phenotype_term:
    preferred_term: Myocardial fibrosis
    term:
      id: HP:0001685
      label: Myocardial fibrosis
  evidence:
  - reference: PMID:40330574
    reference_title: "Mutations in the TCAP gene may lead to restrictive phenotype hypertrophic cardiomyopathy with poor prognosis: case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Endomyocardial biopsy demonstrated cardiomyocyte hypertrophy and focal fibrosis."
    explanation: Histological documentation of myocardial fibrosis in a TCAP variant carrier.
genetic:
- name: TCAP Variants Reported in Hypertrophic Cardiomyopathy
  association: Reported Variants of Disputed Clinical Validity
  relationship_type: DISPUTED
  gene_term:
    preferred_term: TCAP
    term:
      id: hgnc:11610
      label: TCAP
  inheritance:
  - name: Autosomal Dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  features: >-
    The reported HCM alleles are heterozygous missense changes distributed
    across the 167-residue telethonin protein (T137I and R153H in the founding
    Japanese/Korean study; C57W in a Portuguese family), plus one heterozygous
    frameshift (p.Glu12fs) in a 2025 case report. TCAP has only two exons, so
    truncating alleles largely escape nonsense-mediated decay. This is
    mechanistically important because it separates the cardiac claim from the
    skeletal-muscle one: LGMD R7/2G is caused by biallelic loss of function,
    whereas the cardiac alleles are monoallelic and mostly missense. Variant
    interpretation in this gene demands caution — ClinGen found no functional
    support for any reported HCM allele, judged one reported variant to be a
    common population variant, and noted co-occurrence with a pathogenic TNNI3
    variant in one proband and a MYBPC3 VUS in another.
  variants:
  - name: TCAP T137I
    description: >-
      Missense allele identified in a hypertrophic cardiomyopathy proband in the
      founding TCAP cardiomyopathy study; reported to augment telethonin binding
      to titin and calsarcin-1 in vitro.
    gene:
      preferred_term: TCAP
      term:
        id: hgnc:11610
        label: TCAP
  - name: TCAP R153H
    description: >-
      Second missense allele found in a hypertrophic cardiomyopathy proband in
      the same study, with the same reported gain-of-interaction behaviour.
    gene:
      preferred_term: TCAP
      term:
        id: hgnc:11610
        label: TCAP
  - name: TCAP C57W
    description: >-
      Missense allele reported in a small Portuguese HCM family after exclusion
      of eleven established HCM genes; very low population frequency, high
      cross-species conservation, in silico predictions of damage, and a
      co-segregation pattern within the family. No functional assay was
      performed.
    gene:
      preferred_term: TCAP
      term:
        id: hgnc:11610
        label: TCAP
  - name: TCAP p.Glu12fs
    description: >-
      Heterozygous frameshift producing a truncated telethonin, identified by
      whole exome sequencing in a family with restrictive-phenotype hypertrophic
      cardiomyopathy. The first truncating allele reported in a hypertrophic
      presentation; the authors frame the contribution as possible rather than
      proven.
    gene:
      preferred_term: TCAP
      term:
        id: hgnc:11610
        label: TCAP
  evidence:
  - reference: CGGV:assertion_c35abc20-c04c-49ec-af02-1bd270b0b50b-2022-09-14T160000.000Z
    reference_title: "TCAP / hypertrophic cardiomyopathy (Disputed)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      has been DISPUTED. More evidence is needed to either support or entirely
      refute the role
    explanation: >-
      ClinGen's summary judgement on the TCAP-HCM gene-disease relationship,
      which is why `relationship_type` is DISPUTED rather than CAUSATIVE.
  - reference: CGGV:assertion_c35abc20-c04c-49ec-af02-1bd270b0b50b-2022-09-14T160000.000Z
    reference_title: "TCAP / hypertrophic cardiomyopathy (Disputed)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "As a result of this reevaluation, the classification changed from LIMITED to DISPUTED."
    explanation: >-
      Records that the classification was actively downgraded in 2022 by the
      Hereditary Cardiovascular Disorders GCEP, not merely never upgraded.
  - reference: CGGV:assertion_c35abc20-c04c-49ec-af02-1bd270b0b50b-2022-09-14T160000.000Z
    reference_title: "TCAP / hypertrophic cardiomyopathy (Disputed)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The TCAP gene was first associated with hypertrophic cardiomyopathy (HCM)
      in 2004 with missense variants found in 2 probands (Hayashi et al, PMID
      15582318).
    explanation: >-
      ClinGen's enumeration of the primary case-level evidence base for the
      cardiac claim.
  - reference: PMID:30681346
    reference_title: Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The majority of genes previously reported as causative of HCM and commonly
      included in diagnostic tests have limited or no evidence of disease
      association.
    explanation: >-
      The systematic ClinGen HCM gene curation that placed TCAP outside the
      definitive/moderate tiers; supports treating a TCAP finding on an HCM
      panel with caution.
  - reference: PMID:37752589
    reference_title: TCAP gene is not a common cause of cardiomyopathy in Iranian patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the cohort of this study, we identified only one intronic variant
      c.111-42G > A in one of the HCM patients that were predicted as
      polymorphism by in-silico analysis.
    explanation: >-
      A dedicated TCAP screen of 40 HCM/DCM patients returned no pathogenic
      allele, adding negative case-level evidence. PARTIAL because the cohort is
      small and single-population.
  - reference: PMID:37752589
    reference_title: TCAP gene is not a common cause of cardiomyopathy in Iranian patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pathogenic mutations in TCAP may cause diseases including limb-girdle
      muscular dystrophy 2G (LGMD-2G), DCM, HCM, intestinal pseudo-obstruction,
      and telethonin deficiency. However, a large number of affected patients
      were clinically diagnosed with limb-girdle 2G compared to other presenting
      phenotypes.
    explanation: >-
      Frames the TCAP allelic series and makes explicit that the skeletal-muscle
      phenotype dominates the reported variant literature — the named-entity
      hazard this entry guards against.
diagnosis:
- name: Echocardiography
  description: >-
    First-line imaging: establishes unexplained left ventricular hypertrophy,
    characterises its distribution (asymmetric/septal in the reported carriers),
    grades diastolic function, and documents atrial size. It is also the
    modality in which the sigmoidal septal contour of Z-disc HCM was defined.
  diagnosis_term:
    preferred_term: echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  evidence:
  - reference: PMID:40330574
    reference_title: "Mutations in the TCAP gene may lead to restrictive phenotype hypertrophic cardiomyopathy with poor prognosis: case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Transthoracic echocardiography and cardiac magnetic resonance imaging
      (CMR) revealed non-obstructive hypertrophic cardiomyopathy (HCM) with
      severe diastolic dysfunction
    explanation: Worked example of echocardiography establishing the phenotype in a TCAP carrier.
  - reference: PMID:17097056
    reference_title: Echocardiographic-determined septal morphology in Z-disc hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Blinded to the Z-disc genotype status, the septal contour was graded
      qualitatively using standard transthoracic echocardiography.
    explanation: >-
      Documents transthoracic echocardiography as the method by which septal
      morphology is assessed in Z-disc HCM.
- name: Cardiac Magnetic Resonance Imaging
  description: >-
    CMR confirms the hypertrophy distribution, distinguishes non-obstructive
    from obstructive disease, and characterises the myocardium; in the reported
    frameshift carrier it was used alongside echocardiography to establish the
    restrictive-phenotype HCM diagnosis.
  diagnosis_term:
    preferred_term: cardiac magnetic resonance imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:40330574
    reference_title: "Mutations in the TCAP gene may lead to restrictive phenotype hypertrophic cardiomyopathy with poor prognosis: case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Transthoracic echocardiography and cardiac magnetic resonance imaging
      (CMR) revealed non-obstructive hypertrophic cardiomyopathy (HCM) with
      severe diastolic dysfunction, biatrial enlargement, preserved ejection
      fraction, and normal chamber size.
    explanation: CMR contribution to the diagnosis in the one detailed TCAP HCM case.
- name: Endomyocardial Biopsy
  description: >-
    Not routine in HCM, but in the single detailed TCAP case biopsy confirmed
    cardiomyocyte hypertrophy with focal fibrosis and helped exclude infiltrative
    causes of a restrictive physiology.
  diagnosis_term:
    preferred_term: endomyocardial biopsy
    term:
      id: NCIT:C51674
      label: Endomyocardial Biopsy
  evidence:
  - reference: PMID:40330574
    reference_title: "Mutations in the TCAP gene may lead to restrictive phenotype hypertrophic cardiomyopathy with poor prognosis: case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Endomyocardial biopsy demonstrated cardiomyocyte hypertrophy and focal fibrosis."
    explanation: Worked example of biopsy findings in a TCAP variant carrier with HCM.
- name: Cardiomyopathy Multigene Panel or Exome Sequencing
  description: >-
    Molecular testing is what defines this entity, because the clinical
    phenotype mirrors myofilament HCM. TCAP appears on legacy sarcomere/Z-disc
    panels and every reported cardiac allele was found by sequencing after the
    established genes were excluded. Critically, a TCAP variant returned by such
    a panel should NOT by itself be reported as a molecular diagnosis of HCM:
    ClinGen classifies the gene-disease relationship as Disputed, and the
    published variants lack functional support. Look actively for a second,
    better-supported variant — co-occurrence with a pathogenic TNNI3 variant and
    with a MYBPC3 VUS is documented in the TCAP HCM literature.
  diagnosis_term:
    preferred_term: cardiomyopathy multigene panel or exome sequencing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:19035361
    reference_title: Diagnostic yield, interpretation, and clinical utility of mutation screening of sarcomere encoding genes in Danish hypertrophic cardiomyopathy patients and relatives.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Index patients were screened for mutations in all coding regions of 10
      sarcomere genes (MYH7, MYL3, MYBPC3, TNNI3, TNNT2, TPM1, ACTC, CSRP3,
      TCAP, and TNNC1) and five exons of TTN.
    explanation: >-
      Documents TCAP's inclusion on the sarcomere/Z-disc gene panels used for
      HCM family screening.
  - reference: PMID:32565061
    reference_title: Identification of a novel titin-cap/telethonin mutation in a Portuguese family with hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After exclusion of mutations in eleven HCM disease genes, we performed
      direct sequencing of the TCAP gene encoding the Z-disk protein titin-cap
      (also known as telethonin).
    explanation: >-
      Shows the diagnostic position of TCAP: a candidate examined only after the
      established HCM genes are negative.
  - reference: PMID:30681346
    reference_title: Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Classification of HCM genes and variants is critical, as misclassification
      can lead to genetic misdiagnosis.
    explanation: >-
      The interpretive caveat that must accompany a TCAP result on an HCM panel,
      given the Disputed validity classification.
  - reference: CGGV:assertion_c35abc20-c04c-49ec-af02-1bd270b0b50b-2022-09-14T160000.000Z
    reference_title: "TCAP / hypertrophic cardiomyopathy (Disputed)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Furthermore, 1 variant (2 probands) is common in the population (Bos et
      al, 2006, PMID 16352453), and 2 co-occurred with other variants
    explanation: >-
      The concrete reason to keep looking after a TCAP hit: reported alleles
      include a common population variant and cases with a second,
      better-supported variant elsewhere.
- name: Family Evaluation and Cascade Clinical Screening
  description: >-
    Because a TCAP variant cannot carry a genetic diagnosis on its own,
    phenotype-based family evaluation retains primacy: clinical assessment with
    ECG and echocardiography in first-degree relatives, repeated over time.
    Danish HCM family-screening data show mutation status and clinical criteria
    disagree substantially in both directions, which is exactly the situation in
    a Disputed-gene family.
  diagnosis_term:
    preferred_term: cascade clinical and electrocardiographic family screening
    term:
      id: NCIT:C38053
      label: Electrocardiography
  evidence:
  - reference: PMID:19035361
    reference_title: Diagnostic yield, interpretation, and clinical utility of mutation screening of sarcomere encoding genes in Danish hypertrophic cardiomyopathy patients and relatives.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In relatives, 29.9% of mutation carriers did not fulfil any clinical
      diagnostic criterion, and in 37.5% of relatives without a mutation, one or
      more criteria was fulfilled.
    explanation: >-
      Quantifies the genotype-phenotype discordance that makes ongoing clinical
      surveillance necessary alongside (not instead of) genetic testing.
differential_diagnoses:
- name: Myofilament (sarcomeric) hypertrophic cardiomyopathy
  description: >-
    The definitive HCM genes — MYBPC3, MYH7, TNNT2, TNNI3, TPM1, ACTC1, MYL2,
    MYL3 — account for the overwhelming majority of genotyped HCM and are
    clinically indistinguishable from the reported TCAP cases. This is the
    primary differential and, given the Disputed status of TCAP, the more likely
    explanation whenever both are on the table.
  distinguishing_features:
  - Only genotype separates them; MLP/TCAP-associated HCM clinically mimics myofilament HCM.
  - Septal contour differs at the class level (Z-disc HCM sigmoidal, myofilament HCM more often reverse-curvature), but this is a group tendency, not a patient-level discriminator.
  - A definitive-gene variant in the same patient should be regarded as the diagnosis; TCAP co-occurrence with a pathogenic TNNI3 variant is documented.
  disease_term:
    preferred_term: familial hypertrophic cardiomyopathy
    term:
      id: MONDO:0024573
      label: familial hypertrophic cardiomyopathy
  evidence:
  - reference: PMID:16352453
    reference_title: Genotype-phenotype relationships involving hypertrophic cardiomyopathy-associated mutations in titin, muscle LIM protein, and telethonin.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MLP/TCAP-HCM phenotypically mirrors myofilament-HCM and is more severe
      than the subset of patients who still remain without a disease
    explanation: Establishes that phenotype alone cannot separate TCAP-attributed HCM from sarcomeric HCM.
- name: TCAP-related autosomal recessive limb-girdle muscular dystrophy (LGMD R7/2G)
  description: >-
    The best-evidenced TCAP disease is skeletal, not cardiac: ClinGen classifies
    TCAP-LGMD as Definitive, with biallelic loss of function as the expected
    mechanism. Most reported TCAP variants in the literature belong to this
    entity. It is listed here specifically as a named-entity-confusion guard: a
    TCAP paper or variant record is far more likely to be about LGMD R7 than
    about CMH25.
  distinguishing_features:
  - Autosomal recessive with biallelic loss-of-function alleles, versus heterozygous (mostly missense) alleles in the cardiac reports.
  - Presents with progressive proximal muscle weakness in the second decade and raised creatine kinase, not with unexplained left ventricular hypertrophy.
  - ClinGen validity is Definitive for LGMD versus Disputed for hypertrophic cardiomyopathy.
  disease_term:
    preferred_term: autosomal recessive limb-girdle muscular dystrophy type 2G
    term:
      id: MONDO:0011170
      label: autosomal recessive limb-girdle muscular dystrophy type 2G
  evidence:
  - reference: CGGV:assertion_f3c6c72e-7c2b-42d4-963b-aeddbbe0e4fc-2024-08-14T190000.000Z
    reference_title: "TCAP / autosomal recessive limb-girdle muscular dystrophy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      TCAP | HGNC:11610 | autosomal recessive limb-girdle muscular dystrophy |
      MONDO:0015152 | AR | Definitive
    explanation: >-
      ClinGen classifies the TCAP-LGMD relationship as Definitive with autosomal
      recessive inheritance, in contrast to the Disputed autosomal dominant
      cardiac claim.
  - reference: CGGV:assertion_f3c6c72e-7c2b-42d4-963b-aeddbbe0e4fc-2024-08-14T190000.000Z
    reference_title: "TCAP / autosomal recessive limb-girdle muscular dystrophy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The mechanism for disease is expected to be biallelic loss of function."
    explanation: >-
      The mechanistic contrast that keeps the two entities separate: biallelic
      loss of function in LGMD versus monoallelic missense alleles reported in
      the cardiac literature.
- name: TCAP-related dilated cardiomyopathy
  description: >-
    The same gene has been reported in dilated cardiomyopathy, with ClinGen
    classifying that relationship as Limited. The founding study proposed that
    the direction of the binding change distinguishes the two cardiac
    phenotypes, so the DCM literature is mechanistically adjacent but is a
    different entity and must not be used as evidence for the hypertrophic
    phenotype.
  distinguishing_features:
  - Left ventricular dilation with reduced ejection fraction, versus hypertrophy with preserved ejection fraction.
  - The reported DCM allele (E132Q) impaired telethonin binding to MLP, titin, and calsarcin-1; the HCM alleles augmented binding to titin and calsarcin-1.
  - ClinGen validity is Limited for dilated cardiomyopathy versus Disputed for hypertrophic cardiomyopathy — both weak, but curated separately.
  disease_term:
    preferred_term: dilated cardiomyopathy
    term:
      id: MONDO:0005021
      label: dilated cardiomyopathy
  evidence:
  - reference: CGGV:assertion_4c8ab9d8-919a-443f-b027-5aec92b273d1-2025-04-18T040000.000Z
    reference_title: "TCAP / dilated cardiomyopathy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      TCAP | HGNC:11610 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited
    explanation: >-
      ClinGen curates TCAP-DCM separately from TCAP-HCM, at a different
      (Limited) validity level.
  - reference: PMID:15582318
    reference_title: Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the DCM-associated mutations impair the interaction of Tcap with MLP,
      titin, and calsarcin-1
    explanation: >-
      The proposed molecular basis for separating the dilated from the
      hypertrophic TCAP phenotype.
progression:
- phase: Genotype-positive, phenotype-negative relative
  notes: >-
    A relative found to carry a TCAP variant during cascade testing is in an
    unusually uncertain position, because the gene-disease relationship itself
    is Disputed: the variant may carry no risk at all. Danish HCM family data
    show that clinical criteria and mutation status disagree in both directions,
    so surveillance should be driven by family phenotype rather than by the TCAP
    result.
  evidence:
  - reference: PMID:19035361
    reference_title: Diagnostic yield, interpretation, and clinical utility of mutation screening of sarcomere encoding genes in Danish hypertrophic cardiomyopathy patients and relatives.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In relatives, 29.9% of mutation carriers did not fulfil any clinical
      diagnostic criterion
    explanation: >-
      Documents genotype-positive phenotype-negative status as a common state in
      HCM families. PARTIAL because the figure is panel-wide, not TCAP-specific.
- phase: Late-onset overt hypertrophic cardiomyopathy
  notes: >-
    In the only co-segregating family reported, both affected members declared
    late, with moderate asymmetric hypertrophy, atrial fibrillation, and
    preserved-EF heart failure, and were assessed as at low risk of sudden
    cardiac death.
  evidence:
  - reference: PMID:32565061
    reference_title: Identification of a novel titin-cap/telethonin mutation in a Portuguese family with hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both affected members of this family presented with late-onset HCM,
      moderate asymmetric left ventricular hypertrophy, atrial fibrillation and
      heart failure with preserved ejection fraction and low risk of sudden
      cardiac death.
    explanation: The only description of onset timing and risk profile in a TCAP HCM family.
- phase: Progression to advanced heart failure
  notes: >-
    At the severe end of the reported spectrum, a frameshift carrier with
    restrictive-phenotype HCM deteriorated over roughly a year despite treatment
    and was listed for transplantation. Whether this trajectory is
    TCAP-attributable or coincidental cannot be determined from one case.
  evidence:
  - reference: PMID:40330574
    reference_title: "Mutations in the TCAP gene may lead to restrictive phenotype hypertrophic cardiomyopathy with poor prognosis: case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Despite interventions, the patient's cardiac function progressively
      deteriorated, leading to his placement on the heart transplant waiting
      list 1 year later.
    explanation: Documents the severe end of the reported outcome range.
treatments:
- name: Genetic Counseling and Family Evaluation
  description: >-
    Counseling must convey that TCAP-HCM is a Disputed gene-disease relationship:
    a TCAP variant is not, on current evidence, a basis for predictive testing or
    for reassuring a variant-negative relative. Family evaluation should proceed
    on the standard nonsyndromic-HCM footing, driven by phenotype.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301725
    reference_title: Nonsyndromic Hypertrophic Cardiomyopathy Overview.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Inform genetic counseling of family members of an individual with nonsyndromic HCM."
    explanation: >-
      GeneReviews establishes family genetic counseling as a core component of
      nonsyndromic HCM care. Evidence source is OTHER because GeneReviews is an
      expert-authored review resource.
  - reference: CGGV:assertion_c35abc20-c04c-49ec-af02-1bd270b0b50b-2022-09-14T160000.000Z
    reference_title: "TCAP / hypertrophic cardiomyopathy (Disputed)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      has been DISPUTED. More evidence is needed to either support or entirely
      refute the role
    explanation: >-
      The validity statement that has to be communicated in counseling before a
      TCAP result is used for any family decision.
- name: Anticoagulation for Atrial Fibrillation
  description: >-
    Atrial fibrillation is curated as a phenotype of this entity - it occurred in
    both affected carriers of the Portuguese p.C57W allele, and biatrial
    enlargement was present in the frameshift proband - and in hypertrophic
    cardiomyopathy its presence is itself the indication for anticoagulation,
    rather than being filtered through the risk scores used in atrial
    fibrillation without a cardiomyopathy substrate. It is recorded here because
    it is the management consequence of a phenotype this entry already asserts,
    and because applying the ordinary risk-score gate is a common and
    consequential error.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: anticoagulant agent
      term:
        id: NCIT:C263
        label: Anticoagulant Agent
  target_phenotypes:
  - preferred_term: Atrial fibrillation
    term:
      id: HP:0005110
      label: Atrial fibrillation
  evidence:
  - reference: PMID:32565061
    reference_title: Identification of a novel titin-cap/telethonin mutation in a Portuguese family with hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "moderate asymmetric left ventricular hypertrophy, atrial fibrillation and heart failure with preserved ejection fraction"
    explanation: >-
      Documents the atrial fibrillation that constitutes the indication. PARTIAL
      because the source records the arrhythmia and does not report
      anticoagulation, its outcome, or any thromboembolic event in these
      carriers.
  notes: >-
    Deliberately unsourced at the TCAP level and bound at drug-class rather than
    agent level. No TCAP-specific anticoagulation study exists, the cited report
    does not state whether these carriers were anticoagulated, and the choice
    between a direct oral anticoagulant and a vitamin K antagonist is not
    genotype-determined. The indication itself is guideline-directed management
    for hypertrophic cardiomyopathy with atrial fibrillation, so no snippet is
    claimed for it. Note this is management of a curated phenotype, not a claim
    that TCAP variants cause thromboembolism.
- name: Heart Transplantation for End-Stage Disease
  description: >-
    For the minority who progress to refractory heart failure despite
    guideline-directed therapy, transplantation is the endpoint of management,
    as in the reported frameshift carrier. There is no TCAP-directed therapy.
  treatment_term:
    preferred_term: heart transplantation
    term:
      id: NCIT:C15246
      label: Heart Transplantation
  evidence:
  - reference: PMID:40330574
    reference_title: "Mutations in the TCAP gene may lead to restrictive phenotype hypertrophic cardiomyopathy with poor prognosis: case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "leading to his placement on the heart transplant waiting list 1 year later"
    explanation: Transplant listing as the management endpoint in the one reported severe TCAP HCM case.
discussions:
- discussion_id: tcap_hcm_gene_disease_validity_disputed
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - "pathophysiology#Telethonin Z-Disc Titin-Capping and Stretch-Sensor Perturbation"
  prompt: >-
    Is TCAP a genuine hypertrophic cardiomyopathy gene at all, or is CMH25 an
    artefact of pre-genomic candidate-gene sequencing?
  rationale: >-
    ClinGen's Hereditary Cardiovascular Disease GCEP downgraded TCAP-HCM from
    Limited to Disputed in September 2022. The case-level base is roughly eight
    probands over four publications; no reported variant has functional support;
    one variant (2 probands) is common in the population; two probands carried a
    second variant (a pathogenic TNNI3 variant, and a MYBPC3 VUS). A dedicated
    2023 TCAP screen of 40 Iranian cardiomyopathy patients found no pathogenic
    allele. Dismech curates the entity because MONDO:0011843 exists and clinical
    panels still return TCAP variants, but the whole pathograph in this entry is
    conditional on the association being real, and every node is tagged
    HYPOTHETICAL or PROVISIONAL accordingly.
  proposed_experiments:
  - experiment_id: exp_tcap_hcm_case_control_burden
    name: Case-control rare-variant burden test for TCAP in hypertrophic cardiomyopathy
    description: >-
      Compare the burden of rare TCAP variation in large sequenced hypertrophic
      cardiomyopathy cohorts against ancestry-matched population reference data
      (gnomAD), with the definitive-gene carriers excluded so a residual TCAP
      signal is not confounded by a co-occurring sarcomere variant.
    supporting_outcome:
    - A significant excess of rare TCAP variation in cases would move the gene-disease relationship above Disputed.
    refuting_outcome:
    - Absence of excess burden at adequate power would support refuting the association outright.
  - experiment_id: exp_tcap_hcm_isogenic_allele_series
    name: Isogenic human cardiomyocyte allele series for the reported TCAP HCM variants
    description: >-
      Knock the reported alleles (T137I, R153H, C57W, p.Glu12fs) into a common
      hiPSC background and phenotype the derived cardiomyocytes and engineered
      heart tissues for hypertrophy, sarcomere organisation, and relaxation.
    supporting_outcome:
    - A reproducible hypertrophic or diastolic phenotype attributable to the allele would supply the missing functional evidence.
    refuting_outcome:
    - Indistinguishable phenotype from isogenic wild type would argue the alleles are benign.
  - experiment_id: exp_tcap_hcm_rephenotyping_published_probands
    name: Contemporary re-sequencing of the published TCAP HCM probands
    description: >-
      Re-analyse the originally reported probands with current
      cardiomyopathy panels or genome sequencing to establish whether a
      better-supported variant in another gene explains each case.
    refuting_outcome:
    - Recovery of a definitive-gene variant in most probands would collapse the residual case-level evidence for TCAP.
  evidence:
  - reference: CGGV:assertion_c35abc20-c04c-49ec-af02-1bd270b0b50b-2022-09-14T160000.000Z
    reference_title: "TCAP / hypertrophic cardiomyopathy (Disputed)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "As a result of this reevaluation, the classification changed from LIMITED to DISPUTED."
    explanation: The classification change that frames this controversy.
  - reference: PMID:37752589
    reference_title: TCAP gene is not a common cause of cardiomyopathy in Iranian patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings suggest that the TCAP gene pathogenic mutations might not
      be a common cause of cardiomyopathies among Iranian patients.
    explanation: Independent negative cohort evidence contributing to the dispute.
- discussion_id: tcap_hcm_mechanism_unknown
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - "pathophysiology#Altered Z-Disc Signalosome Output"
  prompt: >-
    What, mechanistically, does an HCM-associated TCAP allele do to the
    cardiomyocyte downstream of the Z-disc?
  rationale: >-
    The only mechanistic data are qualitative yeast two-hybrid and GST pull-down
    results from 2004 showing augmented telethonin binding to titin and
    calsarcin-1. Nothing downstream has been measured: no calcineurin activity,
    no NFAT nuclear translocation, no hypertrophic gene program, no
    sarcomere-organisation phenotype, no contractile or relaxation measurement
    in any TCAP-HCM cell, tissue, or animal model. ClinGen states plainly that
    the mechanism is unknown. The Z-disc signalosome node in this entry is
    therefore a placeholder that names the proposed route rather than a
    curated mechanism.
  proposed_experiments:
  - experiment_id: exp_tcap_quantitative_zdisc_binding
    name: Quantitative binding measurement of mutant telethonin with its Z-disc partners
    description: >-
      Replace the original qualitative yeast two-hybrid and pull-down assays
      with quantitative affinity measurements (isothermal titration calorimetry
      or surface plasmon resonance) of mutant versus wild-type telethonin
      against titin Z1Z2, muscle LIM protein, and calsarcin-1.
    supporting_outcome:
    - Reproducible, direction-consistent affinity changes would substantiate the gain-of-interaction model.
    refuting_outcome:
    - Affinities indistinguishable from wild type would remove the only mechanistic support for the model.
  - experiment_id: exp_tcap_calcineurin_nfat_readout
    name: Calcineurin-NFAT signalling readout in TCAP knock-in cardiomyocytes
    description: >-
      Measure calcineurin activity, NFAT nuclear translocation, and hypertrophic
      marker gene expression in cardiomyocytes carrying knock-in TCAP HCM
      alleles, closing the untested step between altered calsarcin binding and
      hypertrophic growth.
    supporting_outcome:
    - Allele-dependent calcineurin-NFAT activation would convert the placeholder signalosome node into a curated mechanism.
  - experiment_id: exp_tcap_sarcomere_and_relaxation_phenotyping
    name: Sarcomere ultrastructure and relaxation phenotyping in TCAP engineered heart tissue
    description: >-
      Characterise Z-disc ultrastructure by electron microscopy and measure
      active and passive mechanics in engineered heart tissue carrying each
      reported allele, to test whether the human diastolic phenotype is
      reproduced in vitro.
  evidence:
  - reference: CGGV:assertion_c35abc20-c04c-49ec-af02-1bd270b0b50b-2022-09-14T160000.000Z
    reference_title: "TCAP / hypertrophic cardiomyopathy (Disputed)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The mechanism for disease is unknown."
    explanation: Expert-panel confirmation that no mechanism is established.
  - reference: CGGV:assertion_c35abc20-c04c-49ec-af02-1bd270b0b50b-2022-09-14T160000.000Z
    reference_title: "TCAP / hypertrophic cardiomyopathy (Disputed)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "None of these variants have functional evidence in support of pathogenicity."
    explanation: The absence of allele-level functional data is the concrete gap.
- discussion_id: tcap_mouse_knockout_versus_human_hcm
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - "pathophysiology#Impaired Myocardial Adaptation to Biomechanical Stress"
  prompt: >-
    Does the telethonin-knockout mouse model the human TCAP hypertrophic
    phenotype, given that it is a loss-of-function model that produces
    stress-induced heart failure rather than hypertrophic cardiomyopathy?
  rationale: >-
    The Tcap-null mouse is the only in vivo cardiac model, and it points the
    opposite way from the human cardiac claim on three counts. First, direction
    of effect: the mouse lacks telethonin entirely, whereas the human HCM alleles
    are heterozygous missense changes reported to *augment* Z-disc binding.
    Second, phenotype: the mouse has a structurally and functionally normal heart
    at baseline and decompensates into heart failure with cardiomyocyte apoptosis
    only after biomechanical stress — it does not develop hypertrophic
    cardiomyopathy. Third, the same study explicitly refutes the structural
    premise that telethonin is indispensable for titin anchorage. Any inference
    from this model to CMH25 pathogenesis therefore requires an unstated and
    unverified assumption that loss and gain of Z-disc interaction converge on
    the same disease.
  proposed_experiments:
  - experiment_id: exp_tcap_missense_knockin_mouse
    name: Missense knock-in rather than null mouse model of TCAP cardiomyopathy
    description: >-
      Generate mice carrying the human T137I, R153H, or C57W allele in place of
      a null allele and phenotype for left ventricular hypertrophy, septal
      geometry, and diastolic function.
    supporting_outcome:
    - A hypertrophic phenotype in a missense knock-in would establish allele-appropriate in vivo modelling of CMH25.
    refuting_outcome:
    - A normal heart in the knock-in, in contrast to the stressed null, would show the null mouse does not model the human allele.
  - experiment_id: exp_tcap_null_versus_knockin_stress_comparison
    name: Head-to-head stress phenotyping of null versus missense knock-in genotypes
    description: >-
      Subject Tcap-null and missense knock-in animals to identical biomechanical
      stress protocols and compare hypertrophy, apoptosis, and heart-failure
      endpoints, to test whether loss and altered interaction converge.
  - experiment_id: exp_tcap_human_myocardium_p53_apoptosis
    name: p53-dependent apoptosis assessment in human TCAP-variant myocardium
    description: >-
      Examine explanted or biopsy myocardium from a TCAP variant carrier for
      nuclear telethonin accumulation, p53 stabilisation, and cardiomyocyte
      apoptosis, to test whether the murine mechanoptosis route operates in the
      human disease.
  evidence:
  - reference: PMID:21799151
    reference_title: Telethonin deficiency is associated with maladaptation to biomechanical stress in the mammalian heart.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Telethonin knockout mice do not reveal defective heart development or
      heart function under basal conditions, but develop heart failure following
      biomechanical stress
    explanation: >-
      The model phenotype is stress-induced heart failure, not hypertrophic
      cardiomyopathy — the core of the mismatch.
  - reference: PMID:15582318
    reference_title: Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the HCM-associated mutations augment the ability of Tcap to interact with
      titin and calsarcin-1
    explanation: >-
      The human HCM alleles are reported as gain-of-interaction, the opposite
      direction from the null mouse.
- discussion_id: tcap_hcm_prevalence_and_penetrance_unknown
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What is the prevalence and penetrance of TCAP-attributed hypertrophic
    cardiomyopathy?
  rationale: >-
    Neither is known, and neither can be estimated while the association is
    Disputed. The only figures available are clinic-cohort yields (4 of 389, and
    1 of 239 myofilament-negative probands), which ClinGen has shown are inflated
    by at least one common population variant. No population-based carrier
    frequency, no penetrance estimate, and no natural-history series exist for
    CMH25.
  proposed_experiments:
  - experiment_id: exp_tcap_biobank_carrier_penetrance
    name: Population-biobank carrier frequency and imaging penetrance for TCAP alleles
    description: >-
      Identify carriers of the reported TCAP hypertrophic-cardiomyopathy alleles
      in a population biobank with cardiac magnetic resonance imaging and
      quantify how many show left ventricular hypertrophy, giving an
      ascertainment-free penetrance estimate.
    refuting_outcome:
    - A high carrier frequency with no imaging phenotype would argue the alleles are benign population variation.
  - experiment_id: exp_tcap_registry_natural_history
    name: Multi-registry aggregation of TCAP variant carriers with hypertrophic cardiomyopathy
    description: >-
      Pool TCAP variant carriers across international hypertrophic
      cardiomyopathy registries with standardised phenotyping and follow-up to
      assemble a natural-history series large enough to describe onset, outcome,
      and arrhythmic risk.
  evidence:
  - reference: CGGV:assertion_c35abc20-c04c-49ec-af02-1bd270b0b50b-2022-09-14T160000.000Z
    reference_title: "TCAP / hypertrophic cardiomyopathy (Disputed)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Furthermore, 1 variant (2 probands) is common in the population (Bos et
      al, 2006, PMID 16352453), and 2 co-occurred with other variants
    explanation: >-
      Shows why the published cohort yields cannot be converted into a
      prevalence estimate.
references:
- reference: PMID:20301725
  title: Nonsyndromic Hypertrophic Cardiomyopathy Overview.
  tags:
  - GeneReviews
- reference: CGGV:assertion_c35abc20-c04c-49ec-af02-1bd270b0b50b-2022-09-14T160000.000Z
  title: TCAP / hypertrophic cardiomyopathy (Disputed)

📚

References & Deep Research

References

2

PMID:20301725

Nonsyndromic Hypertrophic Cardiomyopathy Overview.

No top-level findings curated for this source.

CGGV:assertion_c35abc20-c04c-49ec-af02-1bd270b0b50b-2022-09-14T160000.000Z

TCAP / hypertrophic cardiomyopathy (Disputed)

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] 40 citations 2026-08-01T21:16:39.318857

1. Disease Information

1.1 Overview

Hypertrophic cardiomyopathy 25 (CMH25) is the OMIM-designated, gene-indexed form of familial hypertrophic cardiomyopathy attributed to heterozygous missense variation in TCAP, which encodes telethonin (titin-cap, T-cap) — a 19 kDa, 167-amino-acid sarcomeric Z-disc protein. The designation derives from a single 2004 candidate-gene study (Hayashi et al., PMID:15582318) that identified two TCAP missense variants (T137I, R153H) in Japanese HCM probands, supported by in vitro binding assays. Clinically, reported CMH25 is indistinguishable from sarcomeric HCM: asymmetric left ventricular hypertrophy, frequently septal, with dyspnea, syncope, palpitations, chest pain, arrhythmia, and variable risk of heart failure and sudden cardiac death.

MONDO defines it strictly by gene attribution (verified locally with OAK against sqlite:obo:mondo):

def: "Any hypertrophic cardiomyopathy in which the cause of the disease is a mutation in the TCAP gene." [MONDO:patterns/disease_series_by_gene]

Notably, MONDO places MONDO:0011843 under three parents simultaneously — MONDO:0016192 (neuromuscular disease caused by qualitative or quantitative defects of telethonin), MONDO:0016333 (familial dilated cardiomyopathy), and MONDO:0024573 (familial hypertrophic cardiomyopathy) — an ontological reflection of TCAP's phenotypic promiscuity (HCM, DCM, LGMD R7) and of the weak boundary around this entity.

1.2 Key Identifiers

Resource	Identifier	Notes
MONDO	`MONDO:0011843`	hypertrophic cardiomyopathy 25 — verified locally with OAK
OMIM (phenotype)	`607487`	CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 25; CMH25
OMIM (gene)	`604488`	TITIN-CAP; TCAP
HGNC	`hgnc:11610`	TCAP (lowercase prefix per dismech convention)
NCBI Gene	`8557`	TCAP
UniProt	`O15273`	Telethonin, Homo sapiens
MedGen	CUI `C4225408` / UID `895360`	Hypertrophic cardiomyopathy 25 (CMH25)
UMLS	`C4225408`
DOID	`DOID:0110328`
MeSH	`C564388`	supplementary concept record
GARD	`GARD:0024827`
Orphanet	No CMH25-specific code.	Orphanet models the parent as ORPHA:155 "Familial isolated hypertrophic cardiomyopathy" (flagged NON RARE IN EUROPE). TCAP's Orphanet-recognized disease is LGMD R7.
ICD-10	`I42.1` (obstructive HCM) / `I42.2` (other HCM)	Parent-level only — not CMH25-specific; verify before asserting
ICD-11	`BC43.0` Hypertrophic cardiomyopathy	Parent-level only — flagged as unverified in this session
SNOMED CT	233873004 Hypertrophic cardiomyopathy (parent)	Unverified in this session

MONDO synonym set (verified): CMH25; TCAP hypertrophic cardiomyopathy; cardiomyopathy, familial hypertrophic, type 25; cardiomyopathy, hypertrophic, 25; hypertrophic cardiomyopathy caused by mutation in TCAP; hypertrophic cardiomyopathy type 25; cardiomyopathy, familial hypertrophic, 25 (RELATED).

1.3 Provenance of the Evidence Base

All CMH25-specific information is derived from aggregated, disease-level sources, not from individual-patient/EHR data: - Primary case reports and small candidate-gene cohorts (n = 2 probands in the index study; ≤ 8 probands total in all HCM literature per ClinGen). - Curated aggregators: OMIM, MONDO, MedGen, HPO, ClinVar, ClinGen Gene-Disease Validity. - No EHR-derived, registry-derived, or population-cohort dataset exists specifically for CMH25. Any epidemiological figure quoted below is for HCM as a whole.

2. Etiology

2.1 Disease Causal Factors

Asserted cause: heterozygous germline missense variation in TCAP (17q12), inherited autosomal dominantly, producing telethonin with altered Z-disc protein-binding affinity.

Proposed causal mechanism (Hayashi et al. 2004, PMID:15582318) — verbatim from the abstract:

"Two TCAP mutations, T137I and R153H, were found in patients with HCM, and another TCAP mutation, E132Q, was identified in a patient with DCM. It was demonstrated by the qualitative assays that the HCM-associated mutations augment the ability of Tcap to interact with titin and calsarcin-1, whereas the DCM-associated mutations impair the interaction of Tcap with MLP, titin, and calsarcin-1."

"These observations suggest that the difference in clinical phenotype (HCM or DCM) may be correlated with the property of altered binding among the Z-disc components."

This is a gain-of-interaction model for HCM (opposite in sign to the loss-of-interaction DCM model) — mechanistically unusual and, critically, not independently replicated. ClinGen explicitly discounted it ("None of these variants have functional evidence in support of pathogenicity"), presumably because yeast two-hybrid and GST pull-down competition are qualitative in vitro binding assays without cellular or organismal validation. This tension between the published functional claim and the ClinGen assessment should be curated explicitly as a knowledge gap, not silently resolved either way.

2.2 Genetic Risk Factors

Variant (NM_003673.4)	Protein	dbSNP	ClinVar germline classification (as of 2026-08-01)	Review status	gnomAD AF	Source study
c.410C>T	p.Thr137Ile (T137I)	rs773317399	Pathogenic	no assertion criteria provided (1 submitter — OMIM legacy)	not reported	Hayashi 2004, PMID:15582318
c.458G>A	p.Arg153His (R153H)	rs149585781	Conflicting classifications	criteria provided, conflicting	gnomAD 2.1×10⁻⁴; ExAC 1.7×10⁻⁴; TOPMed 5×10⁻⁵	Hayashi 2004, PMID:15582318
c.171C>G	p.Cys57Trp (C57W)	rs369447207	Uncertain significance (3 submitters)	criteria provided, no conflicts	gnomAD 1–2×10⁻⁵	Toste 2020, PMID:32565061
c.208C>T	p.Arg70Trp (R70W)	rs775636212	Uncertain significance (12 submitters)	criteria provided, no conflicts	gnomAD 3×10⁻⁵	Bos 2006, PMID:16352453
c.394G>C	p.Glu132Gln (E132Q)	rs748358368	Uncertain significance (2 submitters)	criteria provided, no conflicts	gnomAD exomes 1×10⁻⁵	Hayashi 2004 (DCM proband)
c.260G>A	p.Arg87Gln (R87Q)	rs121434298	Uncertain significance	criteria provided, no conflicts	gnomAD exomes 19/1,458,643 = 1.30×10⁻⁵ (nfe 1.44×10⁻⁵; sas 1.16×10⁻⁵; eas 2.52×10⁻⁵; afr 2.99×10⁻⁵); gnomAD genomes 1/152,191	Originally DCM1N; OMIM reclassified to VUS
c.157C>T	p.Gln53Ter (Q53X)	rs104894655	Pathogenic/Likely pathogenic	criteria provided, no conflicts	~1×10⁻⁵	LGMD R7 (recessive) — listed under the CMH25 trait label by ClinVar trait propagation, not an HCM allele
c.110_110+1del	—	rs786205076	Pathogenic	criteria provided, no conflicts	not reported	LGMD R7 (recessive)
— (frameshift)	p.Glu12fs	—	not in ClinVar as of this search	—	—	Hu 2025 (RP-HCM), PMID:40330574

Benign/common TCAP variants routinely encountered on HCM panels (do not misclassify): - c.453A>C p.Ala151= (rs1053651): Benign, allele frequency 0.45–0.71 — a common polymorphism. - c.316C>T p.Arg106Cys (rs45578741): Benign/Likely benign, gnomAD 0.008, TOPMed 0.0156. - c.191C>T p.Ser64Leu (rs45458802): Benign, gnomAD 0.0039–0.0042. - c.111-15dup (rs397516860): Benign/Likely benign.

Analytic point worth curating: R153H — one of only two originally asserted CMH25 alleles — sits at gnomAD AF ≈ 2.1×10⁻⁴ (~1 in 2,400 alleles). For a putatively penetrant autosomal-dominant HCM allele, that frequency is an order of magnitude above what is plausible, and it is precisely the class of observation formalized by Walsh et al. 2017 (PMID:27532257): "We found that in some genes previously reported as important causes of a given cardiomyopathy, rare variation is not clinically informative because there is an unacceptably high likelihood of false-positive interpretation."

Variant class distribution: overwhelmingly missense. Alaei et al. 2023 (PMID:37752589) reviewed the whole TCAP literature: "a total of 44 variants were reported for the TCAP gene in the literature where a majority of mutations were found to be missense." Truncating TCAP alleles are the LGMD R7 mechanism (biallelic loss of telethonin), with one heterozygous frameshift (p.Glu12fs) reported in restrictive-phenotype HCM (PMID:40330574).

Somatic vs germline: exclusively germline. No somatic TCAP involvement in cardiomyopathy; TCAP is not a recognized COSMIC/TCGA cancer driver.

Functional consequence: disputed. The published model is gain of protein–protein interaction (HCM) versus loss of interaction (DCM) — see §6. Truncating alleles cause loss of function (telethonin absent on Western blot/IHC in LGMD R7; PMID:34982307, PMID:25724973).

2.3 Modifier Genes / Oligogenic Contribution

This is a substantive issue for CMH25. Two of the small number of reported TCAP-HCM probands carried a second variant in another cardiomyopathy gene, which ClinGen counted as evidence against TCAP causation: - A pathogenic TNNI3 variant co-occurring in the Andersen 2009 cohort (PMID:19035361). - A MYBPC3 VUS co-occurring in Bos 2006 (PMID:16352453).

Andersen et al. also reported broadly that "Six patients carried two disease-associated mutations." In dismech terms, TCAP variants in HCM are better modeled with relationship_type: MODIFIER or SUSCEPTIBILITY than as primary causal genes, pending new evidence.

The mechanistically nearest modifier candidates are TCAP's binding partners: CSRP3/MLP (moderate HCM evidence per ClinGen; interaction documented in PMID:12507422 and PMID:24860983), TTN, MYOZ2/calsarcin-1, and FLNC.

2.4 Environmental Risk Factors

There are no CMH25-specific environmental risk factors in the literature. HCM-generic modifiers apply: age (LVH develops through adolescence/adulthood; CMH25 HPO annotation is adult onset), male sex (male predominance in clinical HCM cohorts), systemic hypertension and obesity as phenotype amplifiers, and intense competitive athletic exertion as a trigger for arrhythmic events, not as a cause of the underlying genotype.

Because telethonin is a mechanosensitive, load-responsive protein (Ibrahim 2013, PMID:23100327: "Both mechanical overload and unloading alter t-tubule structure"; Knöll 2011, PMID:21799151: heart failure develops only "following biomechanical stress"), hemodynamic load is the most biologically defensible candidate environmental modifier for a TCAP-attributed cardiomyopathy. This is an inference from model-organism data, not a human clinical finding — curate as evidence_source: MODEL_ORGANISM.

2.5 Protective Factors

None identified, genetic or environmental. No protective TCAP alleles are reported. Avoidance of burst/high-intensity competitive exertion, and blood-pressure/weight control, are prudential HCM-generic measures without CMH25-specific evidence.

2.6 Gene–Environment Interactions

The only substantive G×E model available is the mechanical-load × telethonin-deficiency interaction, demonstrated in mice and unproven in humans:

"Telethonin knockout mice do not reveal defective heart development or heart function under basal conditions, but develop heart failure following biomechanical stress, owing at least in part to apoptosis of cardiomyocytes, an effect that may also play a role in human heart failure." (Knöll et al. 2011, PMID:21799151)

This is a textbook conditional-penetrance architecture: genotype silent at baseline, unmasked by an environmental/hemodynamic stressor. However, it is a loss-of-function (KO) model, whereas the human HCM hypothesis is gain-of-interaction — the model does not test the human allele class. Curate as HUMAN_MODEL_MISMATCH rather than as supporting evidence.

3. Phenotypes

3.1 Curated HPO Annotation Set for OMIM:607487

The complete HPO annotation for CMH25 (retrieved from the JAX HPO annotation API) is remarkably sparse — derived from the two Hayashi probands only:

HPO ID	Term (OAK-verified label)	Frequency	Category	Source
`HP:0001639`	Hypertrophic cardiomyopathy	2/2 (100%)	Cardiovascular	PMID:15582318
`HP:0001712`	Left ventricular hypertrophy	2/2 (100%)	Cardiovascular	PMID:15582318
`HP:0001716`	Wolff-Parkinson-White syndrome	1/2 (50%)	Cardiovascular	PMID:15582318
`HP:0003581`	Adult onset	2/2	Clinical course	PMID:15582318
`HP:0000006`	Autosomal dominant inheritance	—	Inheritance	PMID:15582318

All five labels verified locally with OAK against sqlite:obo:hp. Denominators of 2 mean these "frequencies" carry essentially no statistical information — do not curate frequency: OBLIGATE/VERY_FREQUENT from a 2/2. Per the dismech frequency-evidence SOP, omit frequency: for these, or record the raw 2/2 in notes.

3.2 Phenotypes from Individual Case Reports (extend the HPO set)

Toste et al. 2020, Portuguese family, p.C57W (PMID:32565061) — verbatim:

"Both affected members of this family presented with late-onset HCM, moderate asymmetric left ventricular hypertrophy, atrial fibrillation and heart failure with preserved ejection fraction and low risk of sudden cardiac death."

Suggested terms: HP:0001670 Asymmetric septal hypertrophy; HP:0005110 Atrial fibrillation; HP:0001635 Congestive heart failure; HP:0003581 Adult onset (all OAK-verified).

Hu et al. 2025, restrictive-phenotype HCM, p.Glu12fs (PMID:40330574) — verbatim:

"Transthoracic echocardiography and cardiac magnetic resonance imaging (CMR) revealed non-obstructive hypertrophic cardiomyopathy (HCM) with severe diastolic dysfunction, biatrial enlargement, preserved ejection fraction, and normal chamber size. Endomyocardial biopsy demonstrated cardiomyocyte hypertrophy and focal fibrosis."

"Despite interventions, the patient's cardiac function progressively deteriorated, leading to his placement on the heart transplant waiting list 1 year later."

Suggested terms: HP:0025168 Left ventricular diastolic dysfunction; HP:0001723 Restrictive cardiomyopathy; HP:0001685 Myocardial fibrosis (all OAK-verified). This is a single case, n=1, and is the only report of an RP-HCM presentation.

Bos et al. 2006 (PMID:16352453) — phenotype severity, verbatim:

"Patients with MLP/TCAP-associated HCM clinically mimicked myofilament-HCM."

"MLP/TCAP-HCM phenotypically mirrors myofilament-HCM and is more severe than the subset of patients who still remain without a disease-causing mutation."

Cohort context: 389 HCM patients, 215 male, mean LV wall thickness 21.6 ± 6 mm.

3.3 HCM-Generic Phenotype Spectrum (inherited from the parent entity)

Applicable to CMH25 by parent-class inheritance, not by CMH25-specific observation. All OAK-verified:

HPO ID	Term	Type	Typical course
`HP:0002094`	Dyspnea	Symptom	Exertional, progressive
`HP:0001279`	Syncope	Symptom	Episodic; exertional; SCD-risk marker
`HP:0001962`	Palpitations	Symptom	Episodic
`HP:0100749`	Chest pain	Symptom	Exertional angina without epicardial CAD
`HP:0030148`	Heart murmur	Clinical sign	Systolic, dynamic, in obstructive HCM
`HP:0032092`	Left ventricular outflow tract obstruction	Physiological	~⅔ of HCM overall, dynamic/provocable
`HP:0011675`	Arrhythmia	Clinical sign	—
`HP:0004756`	Ventricular tachycardia	Clinical sign	NSVT is an SCD-risk marker
`HP:0001645`	Sudden cardiac death	Outcome	The feared endpoint
`HP:0001695`	Cardiac arrest	Outcome	—
`HP:0001644`	Dilated cardiomyopathy	Late stage	"Burnt-out"/end-stage evolution

3.4 Phenotypes of the Other TCAP Disease (LGMD R7) — for Differential/Boundary Curation

Curators must keep these out of the CMH25 entry (they belong to the autosomal-recessive LGMD R7 entity), but should know them for differential purposes: - HP:0003701 Proximal muscle weakness, HP:0003236 Elevated circulating creatine kinase concentration (both OAK-verified). - Phenotypic range is wide: from asymptomatic/paucisymptomatic hyperCKemia to classic limb-girdle weakness, with a facioscapulohumeral-like pattern in some (PMID:36463458, PMID:40195250). - A characteristic imaging sign: "Muscle MRI of four patients revealed consistent sparing of the sartorius muscle in all patients." (PMID:40195250) - Cardiac involvement occurs in a minority of LGMD R7 patients per UniProt's disease annotation — relevant because it means TCAP loss-of-function does not reliably produce cardiomyopathy in humans, a point that further weakens the CMH25 hypothesis.

3.5 Quality of Life

No CMH25-specific QoL data exist. No EQ-5D, SF-36, PROMIS, or HCMSQ (Hypertrophic Cardiomyopathy Symptom Questionnaire) data are reported for TCAP genotype carriers. HCM-generic QoL burden — exertional limitation, activity restriction, ICD-related anxiety, and the psychosocial burden of familial risk — applies by inheritance. In the Toste family, both affected members had HFpEF with preserved functional capacity and low SCD risk, i.e., a comparatively favorable QoL trajectory; the single RP-HCM case (PMID:40330574) had the opposite — progression to transplant listing within a year.

4. Genetic / Molecular Information

4.1 Causal Gene

Attribute	Value
Symbol	TCAP (aliases: T-cap, telethonin, TELE, CMD1N, LGMD2G)
OMIM gene	604488
HGNC	hgnc:11610
NCBI Gene	8557
Cytoband	17q12 — "In human, telethonin maps at 17q12, adjacent to the phenylethanolamine N-methyltransferase gene." (Valle et al. 1997, PMID:9350988, verbatim)
Reference transcript	NM_003673.4
Gene structure	2 exons (small, compact gene)
UniProt	O15273
Protein length	167 aa
Molecular mass	19,052 Da

UniProt O15273 FUNCTION (verbatim): "Muscle assembly regulating factor. Mediates the antiparallel assembly of titin (TTN) molecules at the sarcomeric Z-disk"

UniProt subcellular location: Cytoplasm → myofibril → sarcomere. Tissue specificity: heart and skeletal muscle.

UniProt disease annotations: (1) Cardiomyopathy, familial hypertrophic, 25 (CMH25), MIM #607487; (2) Muscular dystrophy, limb-girdle, autosomal recessive 7 (LGMDR7), MIM #601954 — "Autosomal recessive myopathy with proximal/distal muscle weakness and telethonin absence; cardiac involvement in some patients."

Discovery (Valle et al. 1997, PMID:9350988) — verbatim:

"In this paper we describe a novel 19 kDa sarcomeric protein named telethonin. The cDNA sequence discloses an open reading frame of 167 amino acids that does not resemble any known protein."

"The frequency of specific cDNA clones in different libraries indicates that the telethonin transcript is amongst the most abundant in skeletal muscle."

4.2 Structural Biology of Telethonin

The defining structural insight is the palindromic titin–telethonin assembly (Zou et al. 2006, Nature, PMID:16407954) — verbatim:

"Here we show, using X-ray crystallography, how the amino terminus of the longest filament component, the giant muscle protein titin, is assembled into an antiparallel (2:1) sandwich complex by the Z-disk ligand telethonin. The pseudosymmetric structure of telethonin mediates a unique palindromic arrangement of two titin filaments, a type of molecular assembly previously found only in protein-DNA complexes."

"The model proposed may provide a molecular paradigm of how major sarcomeric filaments are crosslinked, anchored and aligned within complex cytoskeletal networks."

The complex involves the titin Z1Z2 Ig domains and roughly the N-terminal 140 residues of telethonin, joined by intermolecular β-sheet augmentation. Structural context for CMH25 alleles: T137I and R153H fall in the C-terminal region (residues 137, 153 of 167), outside the crystallized N-terminal titin-binding β-sandwich — a structural observation that sits awkwardly with the "augmented titin binding" functional claim and is worth flagging as an open question.

4.3 Post-Translational Modification / Phosphoregulation

Candasamy et al. 2014, JBC (PMID:24280220) — verbatim:

"kinase assays used in conjunction with MS and site-directed mutagenesis confirmed telethonin as a substrate for protein kinase D and Ca(2+)/calmodulin-dependent kinase II in vitro and identified Ser-157 and Ser-161 as the phosphorylation sites."

"Phosphate affinity electrophoresis and MS revealed endogenous telethonin to exist in a constitutively bis-phosphorylated form in isolated adult rat ventricular myocytes and in mouse and rat ventricular myocardium."

"Such partial replacement with S157A/S161A telethonin disrupted transverse tubule organization and prolonged the time to peak of the intracellular Ca(2+) transient and increased its variance."

"These data reveal, for the first time, that cardiac telethonin is constitutively bis-phosphorylated and suggest that such phosphorylation is critical for normal telethonin function, which may include maintenance of transverse tubule organization and intracellular Ca(2+) transients."

Note a curation discrepancy to flag: UniProt O15273 lists a phosphoserine at Ser39, whereas the functional cardiac literature centers on Ser157/Ser161. Both are real; UniProt's feature table is incomplete for the cardiac PKD/CaMKII sites. Cite Candasamy for the cardiac sites.

Mechanistic relevance to CMH25: T137I and R153H both lie in the C-terminal segment immediately flanking the Ser157/Ser161 regulatory module. A defensible (but untested and unpublished as such) hypothesis is that these substitutions perturb PKD/CaMKII phosphoregulation rather than titin binding per se. Curate as a mechanistic_hypotheses entry with status: EMERGING if included at all — it is an inference drawn in this report, not a literature claim.

4.4 Epigenetics

No CMH25-specific epigenetic data. No TCAP-locus methylation, histone-modification, or chromatin-accessibility findings are reported in cardiomyopathy. Generic HCM epigenetic literature (myocardial DNA methylation remodeling, HDAC involvement in hypertrophic signaling) is not gene-attributable to TCAP. ENCODE/Roadmap contain 17q12 regulatory annotations but nothing disease-linked.

4.5 Chromosomal Abnormalities

None reported. CMH25 is a point-variant disorder. 17q12 is a recurrent CNV locus (the 17q12 recurrent deletion/duplication syndrome, associated with HNF1B), but that CNV interval and its phenotype are unrelated to TCAP-mediated cardiomyopathy — do not conflate them. No pathogenic TCAP deletions/duplications are reported in HCM; chromosomal microarray has no role in CMH25 evaluation.

5. Environmental Information

Environmental factors: None established. No toxicant, radiation, pollutant, or occupational exposure is implicated in CMH25. CTD contains no TCAP–cardiomyopathy chemical-gene-disease triad of clinical relevance.
Lifestyle factors: No CMH25-specific data. HCM-generic considerations: high-intensity competitive athletics as an arrhythmic trigger (not a cause); hypertension and obesity as hypertrophy amplifiers; alcohol and dehydration as precipitants of dynamic LVOT obstruction in obstructive HCM.
Infectious agents: Not applicable. CMH25 has no infectious etiology.
Mechanical/hemodynamic load is the only environmental variable with any mechanistic support (see §2.6) — and only from mouse work.

6. Mechanism / Pathophysiology

6.1 Proposed Causal Chain (label explicitly as HYPOTHETICAL)

TCAP missense variant (T137I / R153H)          [MOLECULAR]
   │
   ▼
Altered telethonin Z-disc protein-binding —
"augmented" interaction with titin and calsarcin-1   [MOLECULAR]
   │
   ├─► Perturbed titin/Tcap/MLP mechanosensor output  [MOLECULAR]
   │        │
   │        ▼
   │   Dysregulated calsarcin-1 (MYOZ2)-tethered
   │   calcineurin–NFAT hypertrophic signaling        [CELLULAR]
   │
   ├─► Disrupted T-tubule organization and
   │   Ca²⁺-induced Ca²⁺ release (CICR)               [CELLULAR]
   │
   └─► Altered nuclear p53 turnover → "mechanoptosis" [CELLULAR]
    │
    ▼
   Cardiomyocyte hypertrophy + myocyte apoptosis      [CELLULAR]
    │
    ▼
   Asymmetric LV hypertrophy, myocardial fibrosis,
   diastolic dysfunction                              [TISSUE]
    │
    ▼
   HFpEF, arrhythmia, sudden cardiac death            [ORGANISM]

Every arrow downstream of the first node is imported from telethonin biology in general (KO mice, in vitro, iPSC) rather than demonstrated for the CMH25 alleles. In dismech terms this is exactly the situation HUMAN_MODEL_MISMATCH was designed for.

6.2 The Z-Disc Mechanosensor Complex (upstream node)

Knöll et al. 2002, Cell (PMID:12507422) — verbatim:

"Muscle cells respond to mechanical stretch stimuli by triggering downstream signals for myocyte growth and survival. The molecular components of the muscle stretch sensor are unknown, and their role in muscle disease is unclear."

"MLP interacts with and colocalizes with telethonin (T-cap), a titin interacting protein. Further, a human MLP mutation (W4R) associated with dilated cardiomyopathy (DCM) results in a marked defect in T-cap interaction/localization."

"We propose that a Z disc MLP/T-cap complex is a key component of the in vivo cardiomyocyte stretch sensor machinery, and that defects in the complex can lead to human DCM and associated heart failure."

The Hayashi framing (verbatim from PMID:15582318): "The Z-disc plays a role in establishing the mechanical coupling of sarcomeric contraction and stretching, with the titin/Tcap/MLP complex serving as a mechanical stretch sensor. Tcap interacts with the calsarcin, which tethers the calcineurin to the Z-disc."

Calcineurin–NFAT is therefore the named signaling route to hypertrophy in the CMH25 hypothesis — via calsarcin-1/MYOZ2 anchoring calcineurin at the Z-disc. Suggested GO term: GO:0033173 calcineurin-NFAT signaling cascade (OAK-verified).

MLP/telethonin interaction was independently confirmed by Vafiadaki et al. 2014 (PMID:24860983), cited by ClinGen as part of the experimental (non-genetic) evidence: "In differentiated striated muscles, MLP-b localizes to the sarcomeres and binds directly to Z-disc components, including α-actinin, T-cap and MLP."

6.3 T-Tubule Structure and Excitation–Contraction Coupling (downstream node)

Ibrahim et al. 2013, Hum Mol Genet (PMID:23100327) — verbatim:

"Telethonin (Tcap) is a stretch-sensitive Z-disc protein that binds to proteins in the t-tubule membrane."

"In cardiomyocytes from 3-month-old KO (3mKO), there were isolated t-tubule defects and Ca(2+) transient dysynchrony without whole heart and cellular dysfunction. Ca(2+) spark frequency more than doubled in 3mKO. At 8 months of age (8mKO), cardiomyocytes showed progressive loss of t-tubules and remodelling of the cell surface, with prolonged and dysynchronous Ca(2+) transients."

"Mechanical overload increased the Ca(2+) spark frequency in KO alone, where there was also significantly more t-tubule loss, with a greater deterioration in t-tubule regularity."

"These data suggest that Tcap is a critical, load-sensitive regulator of t-tubule structure and function."

This defines an age-dependent, load-dependent, progressive cellular phenotype — biologically attractive for a late-onset adult cardiomyopathy, but again derived from loss of function.

6.4 Mechanoptosis — Nuclear p53 Turnover

Knöll et al. 2011, Circ Res (PMID:21799151) — verbatim:

"By using a variety of different genetically altered animal models and biophysical experiments we show that contrary to previous views, telethonin is not an indispensable component of the titin-anchoring system, nor is deletion of the gene or cardiac specific overexpression associated with a spontaneous cardiac phenotype. Rather, additional titin-anchorage sites, such as actin-titin cross-links via α-actinin, are sufficient to maintain Z-disk stability despite the loss of telethonin."

"We demonstrate that a main novel function of telethonin is to modulate the turnover of the proapoptotic tumor suppressor p53 after biomechanical stress in the nuclear compartment, thus linking telethonin, a protein well known to be present at the Z-disk, directly to apoptosis ('mechanoptosis')."

"In addition, loss of telethonin mRNA and nuclear accumulation of this protein is associated with human heart failure, an effect that may contribute to enhanced rates of apoptosis found in these hearts."

This paper is doubly important for curation: it supplies the apoptosis mechanism and it explicitly refutes the earlier structural dogma — telethonin is dispensable for titin anchoring, because α-actinin provides redundancy. That redundancy is itself an argument for why heterozygous TCAP missense variants may be phenotypically tolerated, and thus part of why the gene–disease relationship is disputed.

6.5 Human Cellular Model — iPSC-Cardiomyocytes

Handoh et al. 2025, Juntendo Medical Journal 71(4), DOI 10.14789/ejmj.JMJ24-0025-OA (PMC12441175; no PMID assigned — cite by DOI/PMCID): CRISPR-Cas9 TCAP knockdown in human iPSC-derived cardiomyocytes produced significantly decreased contraction velocity, relaxation velocity, and contraction–relaxation duration, plus aberrant Ca²⁺ waves and triggered activity. The authors interpret the result as DCM-like, not HCM-like — another datapoint arguing that TCAP loss of function maps to dilated, not hypertrophic, physiology.

6.6 Protein Dysfunction Summary

Mechanism class	Applies to CMH25?	Evidence
Gain of interaction / altered binding affinity	Proposed	PMID:15582318 (Y2H + GST pull-down; disputed by ClinGen)
Loss of function (haploinsufficiency)	Not the CMH25 model	Biallelic LOF → LGMD R7 (PMID:10655062)
Dominant negative	Speculative; the one heterozygous frameshift (p.Glu12fs, PMID:40330574) could act this way	n=1
Misfolding / aggregation	No evidence	—
Truncated-protein incorporation	Documented in LGMD R7	PMID:25724973: "mutant telethonin can be incorporated into the sarcomere"

6.7 Metabolic, Immune, and Tissue-Damage Mechanisms

Metabolic: No TCAP-specific metabolic defect. HCM-generic energetic-deficiency models (impaired myocardial energetics, reduced PCr/ATP) apply at the parent level and are the rationale for myosin inhibition (mavacamten "restores myocardial energetics").
Immune: No immune involvement. CMH25 is neither autoimmune nor inflammatory.
Tissue damage: Cardiomyocyte apoptosis (GO:0006915, PMID:21799151); interstitial and replacement myocardial fibrosis (HP:0001685; histologically confirmed in the RP-HCM case, PMID:40330574); microvascular ischemia and myocyte disarray are HCM-generic.

6.8 Molecular Profiling

Transcriptomics: No CMH25-specific dataset. TCAP expression is heart- and skeletal-muscle-restricted and among the most abundant muscle transcripts (PMID:9350988); quantified in GTEx, Fagerberg et al. 2014 (PMID:24309898) and Uhlén et al. 2015 (PMID:25613900) — the latter two cited by ClinGen as the expression evidence in the (insufficient) TCAP–HCM case. Loss of telethonin mRNA is reported in human heart failure (PMID:21799151).
Proteomics: Telethonin phospho-proteomics in cardiac myocytes (PMID:24280220). No CMH25 patient proteomic study.
Metabolomics / lipidomics: None.
Single-cell / spatial transcriptomics: No TCAP-cardiomyopathy-specific study. The Human Cell Atlas adult heart atlases contain telethonin expression by cardiomyocyte subtype, but no disease contrast.
Functional genomics screens: No CRISPR/RNAi screen implicates TCAP in a cardiomyopathy-relevant phenotype; DepMap is uninformative (muscle-restricted, non-essential in cancer lines).

6.9 Suggested Ontology Terms (all OAK-verified in this session)

Biological processes (GO): | GO ID | Label | Role in the chain | |---|---|---| | GO:0055003 | cardiac myofibril assembly | Telethonin's core assembly function | | GO:0071260 | cellular response to mechanical stimulus | Mechanosensing node | | GO:0060048 | cardiac muscle contraction | Contractile output | | GO:0006936 | muscle contraction | — | | GO:0033173 | calcineurin-NFAT signaling cascade | Calsarcin-1/calcineurin hypertrophy route | | GO:0072331 | signal transduction by p53 class mediator | "Mechanoptosis" arm | | GO:0006915 | apoptotic process | Cardiomyocyte loss | | GO:0070296 | sarcoplasmic reticulum calcium ion transport | Ca²⁺ handling defect | | GO:0055010 | ventricular cardiac muscle tissue morphogenesis | Remodeling |

Cellular components (GO): GO:0030018 Z disc · GO:0030315 T-tubule · GO:0030017 sarcomere · GO:0005634 nucleus (p53 arm) · GO:0031430 M band (context)

Cell types (CL): CL:0000746 cardiac muscle cell · CL:0002131 regular ventricular cardiac myocyte · CL:0008002 skeletal muscle fiber (LGMD arm)

7. Anatomical Structures Affected

7.1 Organ Level

Primary: heart (UBERON:0000948) — specifically the left ventricle (UBERON:0002084) and interventricular septum (UBERON:0002094), the classic site of asymmetric hypertrophy.
Secondary: left atrium (dilation from chronic diastolic dysfunction; biatrial enlargement documented in the RP-HCM case); pulmonary circulation (post-capillary pulmonary hypertension); systemic circulation (thromboembolism secondary to atrial fibrillation).
Body system: cardiovascular. (Skeletal muscle involvement belongs to LGMD R7, not CMH25.)

7.2 Tissue and Cell Level

Tissue: myocardium (UBERON:0002349); cardiac muscle tissue (UBERON:0001133); cardiac interstitium (fibrotic remodeling).
Cells: cardiac muscle cell (CL:0000746); regular ventricular cardiac myocyte (CL:0002131). Cardiac fibroblasts participate in the fibrotic response secondarily.
Skeletal muscle organ (UBERON:0001630) and skeletal muscle fiber (CL:0008002) — for the TCAP gene-level entry, not CMH25.

7.3 Subcellular Level

Sarcomeric Z-disc (GO:0030018) — the primary lesion site.
Transverse tubule (GO:0030315) — secondary structural target (PMID:23100327, PMID:24280220).
Sarcomere (GO:0030017), nucleus (GO:0005634, p53/mechanoptosis compartment), sarcoplasmic reticulum (Ca²⁺ handling).

7.4 Localization and Lateralization

Bilateral in the sense of biventricular myocardial expression, but the phenotype is characteristically asymmetric — septal-predominant, left-ventricular-predominant hypertrophy (HP:0001670 Asymmetric septal hypertrophy). The Toste family showed "moderate asymmetric left ventricular hypertrophy"; the Hu case showed non-obstructive HCM with normal chamber size. Right ventricular involvement is uncommon and not reported in CMH25.

8. Temporal Development

8.1 Onset

HPO-annotated onset: HP:0003581 Adult onset (2/2 probands).
Toste family: explicitly "late-onset HCM" (PMID:32565061).
Hu case: symptomatic at 47 years (PMID:40330574).
Onset pattern: insidious/chronic. No congenital or pediatric CMH25 presentation is reported. (Contrast: LGMD R7 typically presents in the 2nd–3rd decade; mean onset 16 ± 1.41 y in a Chinese series, PMID:32005491.)

8.2 Progression

Both trajectories reported in the literature, from an evidence base of essentially three families:

Trajectory	Description	Source
Indolent	Late-onset, moderate LVH, AF, HFpEF, low SCD risk; stable functional status	Toste 2020, PMID:32565061
Aggressive	Restrictive physiology, severe diastolic dysfunction, progression to transplant listing within 1 year of presentation	Hu 2025, PMID:40330574
Myofilament-like	Severity mirroring myofilament-positive HCM, i.e., more severe than genotype-negative HCM	Bos 2006, PMID:16352453

Stages: HCM-generic — (i) subclinical/genotype-positive-phenotype-negative; (ii) established LVH with preserved systolic function; (iii) HFpEF ± AF ± obstruction; (iv) end-stage "burnt-out" HCM with systolic dysfunction and LV dilation (HP:0001644).
Rate: variable; typically slow over decades.
Course pattern: progressive, punctuated by episodic events (syncope, arrhythmia).
Duration: chronic, lifelong.

8.3 Patterns

Remission: none spontaneous. Symptomatic and hemodynamic improvement is treatment-induced (myectomy/ablation/mavacamten for obstruction). Structural hypertrophy is not reversed.
Critical periods: adolescence through early adulthood for phenotype emergence in sarcomeric HCM generally — but CMH25's annotated onset is adult, so serial imaging surveillance of at-risk relatives extends well into adult life. The 2024 AHA/ACC guideline (PMID:38718139) frames the surveillance schedule.

9. Inheritance and Population

9.1 Epidemiology

No prevalence or incidence estimate exists for CMH25 specifically. Figures below are for HCM as a whole and for TCAP's share of HCM cohorts.

HCM overall prevalence: ~1 in 500 clinically diagnosed; revised upward to approximately 1 in 200 when subclinical/genotype-positive individuals are counted (Semsarian et al. 2015, JACC 65:1249–1254, PMID:25814232).
TCAP variant yield in HCM cohorts:

Cohort	n	TCAP variants found	Rate	Source
Japanese/Korean HCM	346	2 (T137I, R153H)	0.58%	PMID:15582318
Mayo Clinic HCM (US)	389	4	1.03%	PMID:16352453
Danish HCM	90 index	(TCAP in panel; contributory variant co-occurring with pathogenic TNNI3)	—	PMID:19035361
Iranian HCM+DCM	40	0 pathogenic (1 intronic polymorphism, c.111-42G>A)	0%	PMID:37752589

Bos 2006 verbatim: "Overall, 16 patients (4.1%) harbored a Z-disc mutation: 12 had a MLP mutation and 4 patients a TCAP mutation. No TTN mutations were detected." and "Approximately 4.1% of unrelated patients had HCM-associated MLP or TCAP mutations."

Alaei 2023 verbatim conclusion: "These findings suggest that the TCAP gene pathogenic mutations might not be a common cause of cardiomyopathies among Iranian patients."

Because the underlying gene–disease relationship is disputed, the defensible prevalence statement for a dismech Prevalence record is prevalence_class: UNKNOWN with measure_type: UNKNOWN, and a notes field capturing the ~0.6–1% cohort variant-detection rate with the caveat that these are variant-detection rates, not attributable-cause rates.

9.2 Inheritance

Pattern: Autosomal dominant (HP:0000006; OMIM; ClinGen MOI field records AD). Contrast with autosomal recessive for LGMD R7 — the same gene, two inheritance modes, a point of real clinical confusion.
Penetrance: Unknown and unmeasurable from the available pedigrees. Toste 2020 reported "a co-segregation pattern was detected" in a two-affected-member family — the strongest segregation evidence available for any TCAP-HCM allele, and it is very weak (a 2-informative-meiosis family cannot generate meaningful LOD). Given adult onset, penetrance would at minimum be age-dependent.
Expressivity: Apparently variable — indolent HFpEF (Toste) versus restrictive/transplant-bound (Hu). With n≈8 probands total, "variable expressivity" is more accurately described as "unconstrained by data."
Genetic anticipation: Not applicable (no repeat expansion).
Germline mosaicism: Not reported.
Founder effects: None described for TCAP-HCM alleles. (A founder effect is relevant to LGMD R7 in the Brazilian population, where the disorder was originally mapped — PMID:10655062 — and where most reported cases have historically come from; PMID:34982307 notes reported cases "mostly include patients from Brazil.")
Consanguinity: Relevant to LGMD R7 (recessive), not to CMH25 (dominant).
Carrier frequency: Not meaningful for a dominant condition. For LGMD R7, TCAP LOF allele frequency in gnomAD is on the order of 10⁻⁵ (e.g., Q53X ≈ 1×10⁻⁵).

9.3 Population Demographics

Affected populations: Reported probands are Japanese (Hayashi 2004), North American/predominantly white (Bos 2006), Danish (Andersen 2009), Portuguese (Toste 2020), and Chinese (Hu 2025). No population enrichment is established. The gnomAD distribution of R87Q is essentially pan-ancestry at ~10⁻⁵ (nfe 1.44×10⁻⁵, sas 1.16×10⁻⁵, eas 2.52×10⁻⁵, afr 2.99×10⁻⁵) — i.e., no ancestral clustering.
Geographic distribution: Global, sporadic case reports; no endemic focus.
Sex ratio: No CMH25-specific ratio. HCM cohorts show male predominance (Bos 2006: 215/389 = 55% male). The single RP-HCM case was male; the Toste family included both sexes.
Age distribution: Adult, with reported presentation in the 5th decade.

10. Diagnostics

10.1 Clinical Tests

Modality	Findings in CMH25	Suggested term
Echocardiography	LVH, asymmetric septal hypertrophy, diastolic dysfunction, LVOT gradient assessment (rest + provocation), atrial size	`NCIT:C16525` Echocardiography Test (OAK-verified)
Cardiac MRI	Wall-thickness mapping, late gadolinium enhancement for myocardial fibrosis (`HP:0001685`); in the RP-HCM case CMR established non-obstructive HCM with severe diastolic dysfunction	CMR — no exact NCIT clinical-action term found in the local NCIT adapter; use `NCIT:C16809` MRI family or free-text `preferred_term`
ECG	LVH voltage criteria, repolarization abnormality, and notably Wolff-Parkinson-White pattern (`HP:0001716`) in 1/2 index probands	`NCIT:C38053` Electrocardiography (OAK-verified)
Ambulatory monitoring	NSVT detection for SCD risk stratification; AF detection	—
Endomyocardial biopsy	"cardiomyocyte hypertrophy and focal fibrosis" (PMID:40330574) — myocyte disarray and interstitial fibrosis are the HCM-generic histology	—
Exercise testing / CPET	Functional capacity, provocable obstruction, blood-pressure response (SCD risk marker)	—
Laboratory	NT-proBNP and hs-troponin as HCM-generic prognostic markers. Serum CK is normal in CMH25 (unlike LGMD R7, where `HP:0003236` elevated CK is characteristic) — a useful discriminator	LOINC coding available for BNP/CK

There is no CMH25-specific biomarker. No FDA/BEST-listed biomarker exists for TCAP genotype.

10.2 Genetic Testing

Recommended approach — and the crucial caveat:

TCAP appears on many legacy multigene HCM panels. Because ClinGen classifies TCAP–HCM as DISPUTED, TCAP should not be included on a contemporary diagnostic HCM panel, and TCAP variants should not be reported as diagnostic findings. Ingles et al. 2019 (PMID:30681346) put this bluntly:

"Recent trends to increase gene panel sizes often mean variants in genes with questionable association are reported to patients. Classification of HCM genes and variants is critical, as misclassification can lead to genetic misdiagnosis."

"Of 4191 HCM variants in ClinVar, 31% were in genes with limited or no evidence of disease association."

"The majority of genes previously reported as causative of HCM and commonly included in diagnostic tests have limited or no evidence of disease association. Systematically curated HCM genes are essential to guide appropriate reporting of variants and ensure the best possible outcomes for HCM families."

Test	Utility in CMH25
Targeted HCM gene panel	Standard of care for HCM; TCAP inclusion is discouraged. Where TCAP is on the panel, expect VUS.
WES	Used in the RP-HCM case to find p.Glu12fs (PMID:40330574). Appropriate for panel-negative HCM.
WGS	No specific advantage for a 2-exon gene.
Single-gene TCAP testing	Appropriate only when LGMD R7 is suspected (proximal weakness + hyperCKemia + absent telethonin on IHC), not for isolated HCM.
CMA / karyotype / FISH	No role.
mtDNA testing	No role — but relevant to the differential (mitochondrial cardiomyopathy is an HCM phenocopy).
Repeat expansion testing	No role — but Friedreich ataxia (GAA-FXN) is an HCM phenocopy worth excluding in the right clinical context.

NCIT term: NCIT:C15709 Genetic Testing (OAK-verified).

Omics diagnostics (RNA-seq, proteomics, metabolomics, epigenomics, liquid biopsy): none have an established or investigational diagnostic role in CMH25. Skeletal-muscle telethonin immunohistochemistry/Western blot is diagnostic for LGMD R7 (absent protein — PMID:34982307, PMID:12379311) but has no cardiac counterpart.

10.3 Clinical Criteria

Diagnosis follows the generic HCM criteria — LV wall thickness ≥15 mm (or ≥13 mm with family history / positive genotype) not explained by abnormal loading conditions — per the 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR HCM Guideline (PMID:38718139) and the 2023 ESC cardiomyopathy guideline. There are no CMH25-specific diagnostic criteria. A "CMH25 diagnosis" is, operationally, HCM-by-standard-criteria plus a TCAP variant — and per ClinGen, the second half of that conjunction does not currently license a causal claim.

10.4 Differential Diagnosis

Alternative	Distinguishing features
Sarcomeric HCM (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, ACTC1, MYL2, MYL3)	The 8 definitive genes — always exclude first; far higher prior probability
Cardiac amyloidosis (ATTR/AL)	Low-voltage ECG despite thick walls, apical sparing strain, bone-scintigraphy uptake, monoclonal screen
Fabry disease (GLA)	Low native T1 on CMR, α-galactosidase A activity, X-linked, angiokeratoma/acroparesthesia
Danon disease (LAMP2), PRKAG2 glycogen storage	Marked pre-excitation/WPW — highly relevant here, since WPW (`HP:0001716`) is in the CMH25 HPO set; extreme LVH with conduction disease
RASopathies (Noonan/PTPN11, LEOPARD)	Dysmorphology, pulmonary valve stenosis, short stature
Friedreich ataxia (FXN)	Neurological phenotype
Mitochondrial cardiomyopathy	Maternal inheritance, multisystem involvement, lactate
Hypertensive heart disease / athlete's heart	Load explanation; concentric, regressive with detraining
LGMD R7 (TCAP, recessive)	Same gene; skeletal-muscle-predominant, elevated CK, biallelic (usually truncating) variants

The 2024 AHA/ACC guideline explicitly directs that "HCM genetic testing should include genes for HCM phenocopies."

10.5 Screening

Newborn screening: not applicable.
Carrier screening: not applicable (dominant); relevant only for LGMD R7 in consanguineous families.
Cascade screening: per guideline, "Cascade genetic testing should be extended to first-degree relatives only if a pathogenic variant is identified in the proband." Because essentially all TCAP-HCM variants are VUS or disputed, cascade genetic testing on a TCAP variant is not indicated. First-degree relatives should instead enter clinical/imaging surveillance (ECG + echocardiography at guideline intervals). This is arguably the single most consequential practical statement in this report.

11. Outcome / Prognosis

11.1 Survival and Mortality

No CMH25-specific survival, life-expectancy, or mortality data exist. No registry, no cohort, no Kaplan–Meier curve. Sample sizes (≤8 probands globally) preclude any survival estimate.

HCM-generic context: contemporary HCM cohorts in expert centers report annual mortality approaching that of the general population (~0.5%/yr), with sudden cardiac death, heart failure, and AF-related stroke as the three modes of disease-related death.

11.2 Morbidity and Function

Heart failure with preserved ejection fraction (both reported CMH25 families).
Atrial fibrillation with associated thromboembolic risk (Toste family).
Exertional limitation.
No CMH25-specific ICF disability data, EQ-5D, SF-36, PROMIS, or HCMSQ measurements exist.

11.3 Disease Course / Complications

Reported CMH25 complications: atrial fibrillation, HFpEF, severe diastolic dysfunction with biatrial enlargement, myocardial fibrosis, progression to transplant candidacy. HCM-generic complications additionally include LVOT obstruction, ventricular arrhythmia and SCD, infective endocarditis (rare, with obstruction/SAM), and end-stage systolic evolution.

Recovery potential: none — the structural phenotype does not remit. Symptomatic and hemodynamic recovery is achievable with obstruction-directed therapy; transplantation is curative of the cardiac phenotype only.

11.4 Prognostic Factors and Biomarkers

No CMH25-specific prognostic factor has been validated. The two published families illustrate the extremes and suggest, at most, hypothesis-generating candidates: - Restrictive physiology / severe diastolic dysfunction — associated with the rapidly deteriorating course (PMID:40330574). - Truncating vs missense allele class — the frameshift case was the aggressive one; the missense families were indolent. n=1 vs n=2; this is a hypothesis, not a genotype–phenotype correlation. - HCM-generic SCD-risk factors (family history of SCD, unexplained syncope, massive LVH ≥30 mm, NSVT, abnormal BP response to exercise, apical aneurysm, extensive LGE, low LVEF) and the HCM Risk-SCD calculator apply by parent-class inheritance. - Toste 2020 explicitly characterized their family as "low risk of sudden cardiac death."

12. Treatment

There is no CMH25-specific, genotype-directed therapy. Management is entirely that of hypertrophic cardiomyopathy generally, per the 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR guideline (PMID:38718139). Nothing about a TCAP genotype currently alters management.

12.1 Pharmacotherapy

Treatment	Class / mechanism	Suggested terms (OAK-verified)
Beta-blockers (e.g., metoprolol)	β-adrenergic antagonism → ↓ inotropy/chronotropy, ↑ diastolic filling, ↓ dynamic obstruction. First line for symptomatic obstructive HCM	`treatment_term` `NCIT:C15986` Pharmacotherapy; `therapeutic_agent` `NCIT:C29576` Beta-Adrenergic Antagonist and/or `CHEBI:6904` metoprolol; `therapeutic_modality: SMALL_MOLECULE`
Non-dihydropyridine calcium channel blockers (verapamil)	↓ contractility, improved diastolic relaxation; alternative when β-blockers are not tolerated	`NCIT:C15986` + `NCIT:C333` Calcium Channel Blocker and/or `CHEBI:9948` verapamil
Disopyramide	Class IA antiarrhythmic with potent negative inotropy; added for refractory obstruction	`NCIT:C15986` + `CHEBI:4657` disopyramide
Mavacamten	First-in-class cardiac myosin inhibitor — allosteric inhibition of cardiac myosin ATPase, reducing actin–myosin cross-bridge formation and hypercontractility	`NCIT:C15986` + `NCIT:C174901` Mavacamten; `therapeutic_modality: SMALL_MOLECULE`. (No CHEBI term for mavacamten in the local CHEBI release — use NCIT.)
Anticoagulation (DOAC/warfarin)	Stroke prevention in HCM with AF — recommended irrespective of CHA₂DS₂-VASc	`NCIT:C15986`
Diuretics	Cautious use for congestion in HFpEF; risk of worsening dynamic obstruction	`NCIT:C15986`
Antiarrhythmics (amiodarone)	AF rhythm control	`NCIT:C15986` + `CHEBI:2663` amiodarone

Mavacamten pivotal evidence — EXPLORER-HCM (Olivotto et al., Lancet 2020;396:759–769, PMID:32871100): randomized, double-blind, placebo-controlled phase 3 in 251 patients with symptomatic obstructive HCM over 30 weeks. Primary endpoint met by 45/123 (37%) on mavacamten vs 22/128 (17%) on placebo; difference +19.4% (95% CI 8.7–30.1; p=0.0005). Abstract background (verbatim): "Cardiac muscle hypercontractility is a key pathophysiological abnormality in hypertrophic cardiomyopathy"; interpretation (verbatim): "Treatment with mavacamten improved exercise capacity, LVOT obstruction, NYHA functional class, and health status." Mavacamten requires REMS-governed echocardiographic monitoring for LVEF reduction and is contraindicated in significant systolic dysfunction; CYP2C19 poor-metabolizer status affects exposure (the one genuinely pharmacogenomic consideration in HCM care — PharmGKB/CPIC-relevant, and unrelated to TCAP genotype).

Pharmacogenomics specific to CMH25: none. No TCAP variant is known to influence drug metabolism, efficacy, or toxicity.

12.2 Advanced Therapeutics

Gene therapy: No TCAP-directed program. AAV9-MYBPC3 gene replacement is in early clinical development for MYBPC3-HCM (a template that could in principle extend to other genes, but nothing exists for TCAP).
Gene editing: Preclinical base/prime editing work in sarcomeric HCM; nothing for TCAP.
RNA-based therapies (ASO, siRNA, mRNA): None for TCAP. No conformance to the antisense_oligonucleotide_therapy module.
Cell therapy, immunotherapy: Not applicable.
Targeted therapy: Mavacamten and the next-generation myosin inhibitor aficamten are "targeted" at the sarcomere but are genotype-agnostic — they target the pathophysiology, not the gene.

12.3 Surgical and Interventional

Septal myectomy (extended Morrow procedure) — gold standard for drug-refractory obstructive HCM in experienced centers. NCIT:C51591 Myectomy (OAK-verified); therapeutic_modality: SURGERY.
Alcohol septal ablation — percutaneous alternative in selected anatomy/comorbidity; observational data suggest similar safety and efficacy to myectomy.
ICD implantation — for primary or secondary SCD prevention per risk stratification. NCIT:C80435 Implantable Cardioverter-Defibrillator Placement; device NCIT:C93238 Implantable Cardioverter-Defibrillator (both OAK-verified); therapeutic_modality: DEVICE.
Heart transplantation — for end-stage disease. NCIT:C15246 Heart Transplantation (OAK-verified); therapeutic_modality: SURGERY. This is the documented endpoint in the one reported RP-HCM CMH25 case (PMID:40330574).
AF ablation / left atrial appendage occlusion — as indicated.

12.4 Supportive, Rehabilitative, Counseling

Supportive care: NCIT:C15747 Supportive Care (OAK-verified) — symptom management, volume management, HF care.
Genetic counseling: NCIT:C15240 Genetic Counseling (OAK-verified); therapeutic_modality: BEHAVIORAL. Central to CMH25 management, and unusually delicate: the counselor's job here is largely to explain why a TCAP variant does not establish a diagnosis, why cascade testing on it is not indicated, and why relatives need clinical surveillance regardless. The guideline recommends "evaluation by a genetic counselor... to discuss risk and benefits of genetic testing."
Exercise counseling: contemporary guidelines permit mild-to-moderate recreational exercise; competitive high-intensity athletics require shared decision-making.
Cardiac rehabilitation: increasingly supported in non-obstructive HCM.

12.5 Experimental Treatments

No trial has ever enrolled by TCAP genotype. Relevant HCM-wide programs: aficamten (SEQUOIA-HCM and successors), ninerafaxstat (cardiac mitotrope, non-obstructive HCM), MYBPC3 gene therapy. A curator should not attach any NCT identifier to CMH25 — none is CMH25-specific, and asserting one would misrepresent the evidence.

12.6 Treatment Outcomes and Strategy

Response rates and adverse events: available only at the HCM parent level (see EXPLORER-HCM numbers above; mavacamten's key adverse event is asymptomatic LVEF reduction).
Treatment algorithm: obstructive symptomatic HCM → β-blocker → verapamil (if intolerant) → add disopyramide or mavacamten → septal reduction therapy if refractory. Non-obstructive HCM → symptom-directed HF therapy; consider transplant evaluation for advanced disease. Parallel track: SCD risk stratification → ICD decision. Parallel track: family screening.
Personalized medicine: genotype currently informs family screening, not drug selection, in HCM. For TCAP specifically, genotype informs neither.

13. Prevention

13.1 Primary Prevention

Not achievable — CMH25 is a germline monogenic (putatively) condition. The only primary-prevention options operate at the reproductive level: preimplantation genetic testing (PGT-M) and prenatal diagnosis. Both are inappropriate for a disputed gene–disease relationship with VUS-level alleles, and should not be offered on the basis of a TCAP variant. This is a clinically important negative recommendation.

13.2 Secondary Prevention

Family clinical surveillance is the mainstay: ECG + echocardiography in first-degree relatives at guideline-specified intervals, continued into adult life given CMH25's adult onset. This applies irrespective of TCAP genotype, precisely because the genotype is uninformative.
Early detection of AF (ambulatory/wearable monitoring) to enable timely anticoagulation.
Serial SCD risk restratification.

13.3 Tertiary Prevention

ICD for SCD prevention in risk-stratified patients.
Anticoagulation for AF-related stroke prevention.
Heart-failure guideline-directed therapy and timely transplant referral.
Endocarditis awareness in obstructive disease with mitral involvement.

13.4 Immunization

Not applicable as disease prevention. Routine influenza/COVID-19/pneumococcal vaccination is standard supportive care in chronic heart disease.

13.5 Screening, Risk Stratification, Counseling

Population screening: none.
Genetic screening: cascade testing not indicated on a TCAP VUS (see §10.5).
Risk stratification: HCM Risk-SCD and guideline risk markers apply generically.
Counseling: should explicitly convey the DISPUTED ClinGen classification, the VUS status of essentially all TCAP-HCM alleles, and that surveillance — not genotype — governs family management.

13.6 Public Health / Environmental Interventions / Prophylaxis

No public-health or environmental intervention is relevant. No prophylactic medication prevents phenotype development in genotype-positive individuals — a long-standing unmet need in HCM generally (prior trials of diltiazem and losartan in preclinical sarcomeric HCM were not practice-changing).

14. Other Species / Natural Disease

14.1 Taxonomy and Orthologs

Species	NCBI Taxon	Gene	Notes
Homo sapiens	`NCBITaxon:9606`	TCAP, NCBI Gene 8557, 17q12	—
Mus musculus	`NCBITaxon:10090`	Tcap, MGI:1330233, chromosome 11	Principal model; KO lines available
Rattus norvegicus	`NCBITaxon:10116`	Tcap	Used for cardiomyocyte phosphoregulation work (PMID:24280220)
Danio rerio	`NCBITaxon:7955`	tcap	Telethonin orthologs studied in sarcomere assembly
Xenopus laevis	`NCBITaxon:8355`	tcap	Morpholino knockdown model (PMID:20235223)
Canis lupus familiaris	`NCBITaxon:9615`	TCAP	See below

14.2 Naturally Occurring Disease in Other Species

The single relevant veterinary study is a negative one, and is worth curating as such:

Philipp U, Vollmar A, Distl O. "Evaluation of the titin-cap gene (TCAP) as candidate for dilated cardiomyopathy in Irish wolfhounds." Animal Biotechnology 2008;19:231–236 (PMID:18855248). Verbatim opening: "Dilated cardiomyopathy (DCM) is a myocardial disorder characterized by left ventricular dilatation and impaired systolic contraction. Irish wolfhounds (IW) and other large breed dogs are most commonly disposed to DCM." The study evaluated TCAP as a positional/functional candidate for canine DCM; TCAP was not established as the cause.

Breed (VBO): Irish Wolfhound — a VBO identifier exists for the breed but was not verified in this session; look it up before asserting.
OMIA: No OMIA entry for telethonin-related cardiomyopathy was identified. Unverified — check OMIA directly before asserting absence in a KB entry.
Naturally occurring HCM is common in domestic cats (Felis catus, NCBITaxon:9685), where MYBPC3 variants in Maine Coon and Ragdoll breeds are the established genetic causes — TCAP is not implicated in feline HCM.

14.3 Comparative Biology

Evolutionary conservation: Telethonin is a vertebrate striated-muscle-specific protein, highly conserved across mammals; the Toste variant p.C57W was selected in part because of "high conservation across species" (PMID:32565061).
Comparative pathology divergence — important: mouse Tcap knockout produces no spontaneous cardiac phenotype (PMID:21799151), whereas human biallelic TCAP loss produces skeletal muscular dystrophy (LGMD R7) with only inconsistent cardiac involvement, and human heterozygous missense variants are claimed to produce hypertrophic cardiomyopathy. These three do not line up. The divergence is itself evidence for the disputed status of CMH25 and should be curated as a HUMAN_MODEL_MISMATCH discussion.

14.4 Transmission

Not applicable — no zoonotic potential, no cross-species transmission. CMH25 is a germline genetic condition.

15. Model Organisms

15.1 Available Models

Model	Type	Key findings	Reference
Tcap knockout mouse (MGI:1330233)	Mammalian, germline KO	No baseline cardiac phenotype; heart failure only after biomechanical stress; cardiomyocyte apoptosis; nuclear p53 turnover defect ("mechanoptosis")	Knöll et al. 2011, PMID:21799151
Tcap KO mouse, aged / pressure-overloaded	Mammalian, KO + aortic banding	3-month KO: isolated t-tubule defects, Ca²⁺ transient dyssynchrony, >2× Ca²⁺ spark frequency, no whole-heart dysfunction. 8-month KO: progressive t-tubule loss, cell-surface remodeling, depressed L-type Ca²⁺ current. Overload: greater t-tubule loss and severe loss of cell-surface ultrastructure in KO	Ibrahim et al. 2013, PMID:23100327
Cardiac-specific Tcap overexpression mouse	Mammalian, transgenic	No spontaneous cardiac phenotype	Knöll et al. 2011, PMID:21799151
Adult rat ventricular myocytes + adenoviral S157A/S161A telethonin	In vitro, mammalian primary cells	Non-phosphorylatable telethonin disrupted transverse tubule organization and prolonged the time to peak of the intracellular Ca²⁺ transient and increased its variance	Candasamy et al. 2014, PMID:24280220
Human iPSC-CM, CRISPR-Cas9 TCAP knockdown	Human cellular	Significantly decreased contraction velocity, relaxation velocity, contraction–relaxation duration; aberrant Ca²⁺ waves and triggered activity; authors interpret as DCM-like	Handoh et al. 2025, Juntendo Med J 71(4), DOI 10.14789/ejmj.JMJ24-0025-OA, PMC12441175
Xenopus telethonin morpholino knockdown	Invertebrate-adjacent / amphibian embryo	Telethonin reduction "leads to embryonic paralysis, myocyte defects, and sarcomeric disruption"; full-length mRNA rescues, C-terminally truncated constructs do not; "the telethonin C-terminus is required for assembly, but in a context-dependent manner"	Sadikot et al. 2010, Dev Dyn 239:1124–1135, PMID:20235223
Yeast two-hybrid / GST pull-down	In vitro biochemical	The original CMH25 functional claim: HCM variants augment titin/calsarcin-1 binding	Hayashi et al. 2004, PMID:15582318

15.2 Genetic Model Types Available

Constitutive knockout and cardiac-specific transgenic overexpression are documented. No knock-in mouse carrying the human CMH25 alleles (T137I, R153H, C57W, or p.Glu12fs) has been reported. No conditional/inducible or humanized TCAP line is described in the literature reviewed. IMPC/KOMP/IMSR should be queried directly for current allele availability (not verified in this session).

15.3 Phenotype Recapitulation and Limitations

This is the crux, and it should be stated plainly in any KB entry:

Human CMH25 feature	Recapitulated in models?
Left ventricular hypertrophy	No. Tcap KO mice show no spontaneous hypertrophy; cardiac overexpression likewise produces no phenotype
Asymmetric septal hypertrophy	No
Adult-onset progressive course	Partially — age-dependent t-tubule deterioration in KO mice (3mo → 8mo)
Diastolic dysfunction	Partially/indirectly — prolonged, dyssynchronous Ca²⁺ transients
Load-dependent decompensation	Yes — the strongest recapitulation, in Tcap KO + aortic banding
Cardiomyocyte apoptosis / fibrosis	Yes (apoptosis, KO after stress)
The actual human allele class (heterozygous missense, gain-of-interaction)	NOT MODELED AT ALL

Limitations to record explicitly: 1. Allele-class mismatch. Every animal model is a loss-of-function model; the human CMH25 hypothesis is gain of interaction in the heterozygous state. The models therefore cannot test the disease hypothesis — a textbook kind: HUMAN_MODEL_MISMATCH situation for dismech, not a generic KNOWLEDGE_GAP. 2. Direction-of-phenotype mismatch. Where TCAP perturbation does produce a cardiac phenotype (iPSC-CM knockdown; Tcap KO under stress), the phenotype is dilated/hypocontractile, not hypertrophic. 3. Structural redundancy. Knöll 2011 showed α-actinin-mediated actin–titin cross-links maintain Z-disc stability without telethonin — a built-in buffer that argues against strong dominant effects from a single missense allele. 4. No model addresses the WPW/pre-excitation component of the human annotation.

15.4 Research Applications

Existing models are well suited to studying: Z-disc mechanosensing and load transduction; t-tubule biogenesis, maintenance, and CICR; stretch-induced apoptosis and nuclear p53 handling; telethonin phosphoregulation by PKD/CaMKII; and sarcomere assembly (Xenopus). They are not suited to validating CMH25 causality.

The single highest-value experiment for resolving the CMH25 dispute would be a heterozygous knock-in mouse (or isogenic iPSC-CM line) carrying human T137I or R153H, characterized for hypertrophy at baseline and under pressure overload, with quantitative titin/calsarcin-1 binding measured in situ. Curate this as a proposed_experiments entry attached to the knowledge-gap discussion.

15.5 Model Resources

MGI (MGI:1330233), IMPC, IMSR, KOMP/EuMMCR (allele availability not verified in this session), ZFIN, Xenbase, Alliance of Genome Resources, Cellosaurus (for iPSC lines).

Recommended dismech Curation Decisions

Do not curate CMH25 as an established causal mechanism. Model the pathophysiology chain under mechanistic_hypotheses with status: EMERGING, and have the causal edges opt in via hypothesis_groups.
Add a discussions entry with kind: HUMAN_MODEL_MISMATCH (not KNOWLEDGE_GAP) attached to the "Telethonin Z-Disc Dysfunction" node: evidence exists abundantly in mouse KO, rat myocytes, and human iPSC-CM, but every model tests loss of function while the human hypothesis is heterozygous gain-of-interaction — and the models' cardiac phenotype, when present, is dilated rather than hypertrophic. Include proposed_experiments (heterozygous T137I/R153H knock-in).
Cite the ClinGen DISPUTED assertion as first-class evidence using the cache file already in the worktree: reference: CGGV:assertion_c35abc20-c04c-49ec-af02-1bd270b0b50b-2022-09-14T160000.000Z, supports: REFUTE, evidence_source: OTHER, with a quotable row such as "TCAP | HGNC:11610 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Disputed | SOP9 | Hereditary Cardiovascular Disease Gene Curation Expert Panel | 2022-09-14T16:00:00.000Z".
Omit frequency: on all phenotypes — the HPO denominators are 2/2 and 1/2 from a single paper. Put "2/2 probands, PMID:15582318" in notes.
Genetic block: consider relationship_type: SUSCEPTIBILITY or MODIFIER rather than a plain causal gene assertion, and record the two documented co-occurring variants (pathogenic TNNI3, MYBPC3 VUS) as the reason.
Prevalence: measure_type: UNKNOWN, prevalence_class: UNKNOWN, with the 0.58%/1.03%/0% cohort detection rates in notes — these are variant-detection rates, not attributable-cause rates.
Do not attach clinical trials. No NCT is CMH25-specific.
Consider conforms_to: cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling for the downstream tissue-level node; the electrical module (cardiac_ion_channel_repolarization) does not apply — CMH25 is structural, and the WPW annotation is a single-proband observation, not a channelopathy.
Every PMID cited here must still be run through just fetch-reference and just validate-references before committing. Abstract text in this report was retrieved verbatim from the Europe PMC REST API; the OMIM entries (607487, 604488) returned HTTP 403 and were not read directly — OMIM-attributed content here comes via MONDO, MedGen, HPO, UniProt, and search summaries, so do not quote OMIM text as a verified snippet without fetching it.

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OpenScientist Report

Classifications

Inheritance

Mechanistic Hypotheses

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Progression

Prevalence

Differential Diagnoses

Source YAML

References & Deep Research

References

Deep Research

1. Disease Information

1.1 Overview

1.2 Key Identifiers

1.3 Provenance of the Evidence Base

2. Etiology

2.1 Disease Causal Factors

2.2 Genetic Risk Factors

2.3 Modifier Genes / Oligogenic Contribution

2.4 Environmental Risk Factors

2.5 Protective Factors

2.6 Gene–Environment Interactions

3. Phenotypes

3.1 Curated HPO Annotation Set for OMIM:607487

3.2 Phenotypes from Individual Case Reports (extend the HPO set)

3.3 HCM-Generic Phenotype Spectrum (inherited from the parent entity)

3.4 Phenotypes of the Other TCAP Disease (LGMD R7) — for Differential/Boundary Curation

3.5 Quality of Life

4. Genetic / Molecular Information

4.1 Causal Gene

4.2 Structural Biology of Telethonin

4.3 Post-Translational Modification / Phosphoregulation

4.4 Epigenetics

4.5 Chromosomal Abnormalities

5. Environmental Information

6. Mechanism / Pathophysiology

6.1 Proposed Causal Chain (label explicitly as HYPOTHETICAL)

6.2 The Z-Disc Mechanosensor Complex (upstream node)

6.3 T-Tubule Structure and Excitation–Contraction Coupling (downstream node)

6.4 Mechanoptosis — Nuclear p53 Turnover

6.5 Human Cellular Model — iPSC-Cardiomyocytes

6.6 Protein Dysfunction Summary

6.7 Metabolic, Immune, and Tissue-Damage Mechanisms

6.8 Molecular Profiling

6.9 Suggested Ontology Terms (all OAK-verified in this session)

7. Anatomical Structures Affected

7.1 Organ Level

7.2 Tissue and Cell Level

7.3 Subcellular Level

7.4 Localization and Lateralization

8. Temporal Development

8.1 Onset

8.2 Progression

8.3 Patterns

9. Inheritance and Population

9.1 Epidemiology

9.2 Inheritance

9.3 Population Demographics

10. Diagnostics

10.1 Clinical Tests

10.2 Genetic Testing

10.3 Clinical Criteria

10.4 Differential Diagnosis

10.5 Screening

11. Outcome / Prognosis

11.1 Survival and Mortality

11.2 Morbidity and Function

11.3 Disease Course / Complications

11.4 Prognostic Factors and Biomarkers

12. Treatment

12.1 Pharmacotherapy

12.2 Advanced Therapeutics