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Classifications

Harrison's Part

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Inheritance

2

Autosomal Dominant HP:0000006

CMD1Z is transmitted as an autosomal dominant trait: a single heterozygous missense allele in TNNC1 is sufficient, and the mutant protein is expressed approximately equimolar with wild-type cTnC in patient myocardium, consistent with an altered-function (dominant-negative) rather than haploinsufficiency mechanism. ClinGen's Dilated Cardiomyopathy Gene Curation Expert Panel records autosomal dominant inheritance with Definitive clinical validity.

Autosomal dominant inheritance

Show evidence (3 references)

CGGV:assertion_6ad71467-74c0-4a7c-932d-c5ca5747e59e-2025-05-30T160000.000Z SUPPORT Other

ClinGen Dilated Cardiomyopathy GCEP records autosomal dominant inheritance for the TNNC1 gene-disease relationship, classified Definitive.

PMID:40671656 SUPPORT Human Clinical

"We identified a multigenerational family carrying the TNNC1-c.404A>C variant with autosomal dominant DCM with both systolic and diastolic dysfunctions."

A contemporary multigenerational pedigree demonstrating autosomal dominant segregation of a TNNC1 variant with DCM.

PMID:19808376 SUPPORT Human Clinical

"Mass spectroscopy showed that the mutant cTnC was expressed approximately equimolar with wild-type cTnC."

Direct measurement in patient myocardium that both alleles are expressed, supporting a dominant altered-function mechanism rather than haploinsufficiency.

De Novo and Germline Mosaic

A substantial share of reported TNNC1 variants are de novo rather than inherited, which is why segregation data are scarce for this gene. Recurrence of the same de novo TNNC1 variant in three siblings with lethal infantile DCM established germline mosaicism as a recurrence mechanism relevant to reproductive counseling.

Show evidence (2 references)

PMID:40671656 SUPPORT Human Clinical

"Unlike other sarcomere genes, most reports of TNNC1 variants lack segregation or pedigree data, partly because the majority of the variants described, to date, have been reported as de novo."

Documents that de novo occurrence is the norm rather than the exception for reported TNNC1 variants.

PMID:36814108 SUPPORT Human Clinical

"The identification of the same de novo variant in all affected siblings is suggestive of germline mosaicism in this family."

Establishes germline mosaicism as a recurrence mechanism for an apparently de novo TNNC1 variant.

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Mechanistic Hypotheses

3

Thin-filament calcium-desensitization model

tnnc1_calcium_desensitization_model CANONICAL

Evidence balance 2 support

The canonical model of thin-filament cardiomyopathy holds that DCM-causing troponin and tropomyosin variants lower the Ca2+ sensitivity of the myofilament while hypertrophic variants raise it, so that at any given systolic Ca2+ transient the mutant sarcomere generates less force. Applied to TNNC1, a variant that destabilizes the regulatory N-domain, accelerates Ca2+ dissociation, or perturbs the cTnC structure reduces the fraction of thin filament switched on per beat, producing a hypocontractile ventricle that dilates. This model is directly supported for the TNNC1 variants Y5H and M103I, for the compound-heterozygous D132N allele, for the E135A pedigree variant, and by a knock-in mouse in which engineered Ca2+ desensitization of the cTnC N-domain alone was sufficient to cause early-onset DCM.

Pathograph links

Cardiac Troponin C Variant and Thin-Filament Regulatory Defect -> Altered Myofilament Calcium Sensitivity DIRECT

Altered Myofilament Calcium Sensitivity -> Impaired Cardiomyocyte Contractile Performance DIRECT

Show evidence (2 references)

PMID:17932326 SUPPORT In Vitro

"In vitro functional assays show that, in general, the presence of dilated cardiomyopathy mutations decreases the Ca(2+) sensitivity of contractility, whereas HCM mutations increase it."

States the canonical opposing-Ca2+-sensitivity paradigm that this hypothesis group encodes, and the study then confirms it at the level of thin-filament Ca2+ affinity.

PMID:26379556 SUPPORT Model Organism

"In conclusion, our results suggest that decreasing Ca(2+) sensitivity of the regulatory N-domain of cTnC is sufficient to trigger the development of DCM."

Provides the sufficiency argument for the desensitization model in vivo, though with an engineered rather than a patient-derived TNNC1 allele (see the HUMAN_MODEL_MISMATCH discussion).

Troponin-phosphorylation uncoupling model

tnnc1_phosphorylation_uncoupling_model ALTERNATIVE

Evidence balance 3 support

A competing model, derived principally from explanted human myocardium rather than reconstituted systems, holds that the pathogenic lesion is not the absolute level of myofilament Ca2+ sensitivity but the loss of its regulation. Normally, PKA phosphorylation of troponin I at Ser23/24 during beta-adrenergic stimulation desensitizes the myofilament to Ca2+, accelerating relaxation and supplying inotropic and lusitropic reserve; dephosphorylation reverses this. In myocardium from a G159D carrier the mutant troponin abolished that phosphorylation-dependent shift, and the same abolition is seen for the E135A pedigree variant in reconstituted human cardiac muscle and for M103I in skinned fibres. Under this model the ventricle fails because it cannot respond to sympathetic drive, not because its resting Ca2+ sensitivity is low — indeed in the G159D explanted heart Ca2+ sensitivity was higher than donor myocardium, the opposite of the canonical prediction.

Pathograph links

Cardiac Troponin C Variant and Thin-Filament Regulatory Defect -> Uncoupling of Troponin Phosphorylation from Calcium Sensitivity DIRECT

Uncoupling of Troponin Phosphorylation from Calcium Sensitivity -> Impaired Cardiomyocyte Contractile Performance DIRECT

Uncoupling of Troponin Phosphorylation from Calcium Sensitivity -> Neurohormonal Activation INDIRECT UNKNOWN INTERMEDIATES A myofilament that cannot respond to beta-adrenergic stimulation forces escalating sympathetic drive to maintain output, but the intermediate steps linking myofilament unresponsiveness to systemic neurohormonal activation have not been measured in TNNC1 carriers.

Show evidence (3 references)

PMID:19808376 SUPPORT Human Clinical

"We propose that uncoupling of the relationship between phosphorylation and Ca(2+) sensitivity could be the cause of the dilated cardiomyopathy phenotype."

The primary statement of this alternative model, made from patient myocardium carrying the founding CMD1Z variant.

PMID:40671656 SUPPORT In Vitro

"Using reconstituted human cardiac muscle preparations, we showed that the cTnC-E135A abolishes the myofilament response to PKA-mediated phosphorylation."

Independent replication of the uncoupling mechanism in human cardiac muscle preparations with a different, segregating TNNC1 variant.

PMID:17577574 SUPPORT In Vitro

"We conclude that this DCM mutant significantly blunts the contractile response to phosphorylation and this novel mechanism may contribute to its pathogenic effect."

Reconstituted-fibre demonstration of the same blunted phosphorylation response for G159D, using PKA and PKC phosphomimetics.

Slowed activation-kinetics model

tnnc1_activation_kinetics_model EMERGING

Evidence balance 3 support

A third, kinetic account proposes that the primary defect of at least some TNNC1 variants lies in the rate at which the thin filament switches on rather than in the steady-state force-pCa relationship. G159D troponin incorporated into skinned fibres left Ca2+ sensitivity and cooperativity unchanged but halved the activation rate, which in an intact beating ventricle would truncate systolic force development within the available ejection time. A related kinetic reading comes from in silico modeling of the E135A variant, where a slowed Ca2+ off-rate and slowed myosin detachment predict increased ventricular stiffness alongside reduced ejection fraction. The model is EMERGING because the kinetic parameters have been measured in reconstituted and computational systems rather than in beating human myocardium.

Pathograph links

Cardiac Troponin C Variant and Thin-Filament Regulatory Defect -> Slowed Rate of Thin-Filament Activation DIRECT

Slowed Rate of Thin-Filament Activation -> Impaired Cardiomyocyte Contractile Performance DIRECT

Show evidence (3 references)

PMID:17021793 SUPPORT In Vitro

"Gly159Asp TnC had no significant effect on either the Ca(2+) sensitivity or cooperativity of force generation when compared to wild type. However, the mutation caused a highly significant (ca. 50%) decrease in the rate of activation."

Establishes a kinetic (rate-of-activation) defect that is explicitly dissociated from the steady-state Ca2+ sensitivity change the canonical model predicts.

PMID:17021793 SUPPORT In Vitro

"This represents a novel mechanism by which a cardiomyopathy-causing mutation can affect contractility."

The authors themselves frame the kinetic defect as a mechanism distinct from the established Ca2+-sensitivity paradigm, which is why this group is curated separately rather than folded into the canonical model.

PMID:40671656 SUPPORT Computational

"in silico mathematical modeling showed that this variant affects crossbridge kinetics by decreasing both Ca2+ kOFF-rate constant and myosin detachment rate, which could result in increased ventricular stiffness and reduced ejection fraction"

Computational support for a kinetic route to contractile failure. PARTIAL because the kinetic parameters are modeled rather than measured, and because the direction of the rate change differs from the G159D activation-rate finding.

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Discussions and Knowledge Gaps

3

Does the founding CMD1Z variant G159D cause dilated cardiomyopathy by desensitizing the myofilament to calcium, as the canonical thin-filament model predicts, or by uncoupling troponin phosphorylation from calcium sensitivity — and why do reconstituted systems and native patient myocardium give opposite answers?

CONTROVERSY OPEN tnnc1_mechanism_direction_conflict

Attached to

pathophysiology#Altered Myofilament Calcium Sensitivity pathophysiology#Uncoupling of Troponin Phosphorylation from Calcium Sensitivity

The canonical model, built from reconstituted thin filaments, holds that DCM variants lower and hypertrophic variants raise myofilament Ca2+ sensitivity. For G159D this prediction fails in the one system closest to the disease: in myocytes from an explanted G159D heart the Ca2+ sensitivity was higher than donor myocardium, while in reconstituted fibres it was unchanged and the defect was purely kinetic. The authors of the explanted-tissue study attribute the discrepancy to native post-translational modification state — reconstituted systems lack the endogenous troponin I and troponin T phosphorylation that modulates how a mutation behaves. This matters beyond G159D: it implies that variant-classification pipelines built on reconstituted-system Ca2+ sensitivity may systematically mispredict the direction of effect, and therefore the phenotype, for TNNC1 alleles.

Proposed experiments

Cross-variant force-pCa and PKA panel in one human preparation

tnnc1_cross_variant_human_force_pca_panel

Measure the force-pCa relationship and the PKA response for a panel of TNNC1 variants side by side in the same cTnC-depleted human donor myocardium system, so that direction-of-effect comparisons are not confounded by species or preparation.

Decision criterion

If desensitizing and sensitizing TNNC1 variants both reproduce their published directions in one common human preparation, the discrepancy is genotype-driven; if the directions converge, it was preparation-driven.

Paired phosphorylation-stoichiometry and calcium-sensitivity assay

tnnc1_paired_phosphostoichiometry_calcium_sensitivity

Assay troponin I Ser23/24 phosphorylation stoichiometry alongside each Ca2+-sensitivity measurement, to test directly whether native phosphorylation state accounts for the reconstituted-versus-explanted discrepancy.

Decision criterion

If Ca2+-sensitivity direction tracks measured phosphorylation stoichiometry rather than the variant identity, the uncoupling model subsumes the desensitization result.

Show evidence (2 references)

PMID:19808376 SUPPORT Human Clinical

"The differences between these data and previous in vitro results show that native phosphorylation of troponin I and troponin T and other posttranslational modifications of sarcomeric proteins strongly influence the functional effects of a mutation."

The authors explicitly identify the system-dependence of the measured effect as the source of the conflict, which is the substance of this controversy.

PMID:17021793 SUPPORT In Vitro

"Gly159Asp TnC had no significant effect on either the Ca(2+) sensitivity or cooperativity of force generation when compared to wild type."

The reconstituted-fibre result that disagrees with both the canonical prediction and the explanted-tissue measurement, establishing the three-way discrepancy.

Does the D73N knock-in mouse, whose substitution is explicitly not known to cause human disease, faithfully model the pathophysiology of human TNNC1 dilated cardiomyopathy?

HUMAN MODEL MISMATCH OPEN tnnc1_d73n_mouse_model_mismatch

Attached to

pathophysiology#Altered Myofilament Calcium Sensitivity pathophysiology#Adverse Ventricular Remodeling

The only in vivo model of cTnC-driven dilated cardiomyopathy carries D73N, a substitution the authors engineered to reduce Ca2+ sensitivity and which they state is not known to be associated with heart disease in human patients. It demonstrates sufficiency — desensitizing the cTnC regulatory domain alone produces DCM in a mouse — but it cannot demonstrate necessity or fidelity for the human alleles. The mismatch is not merely formal: the best-studied human allele, G159D, sits in the structural C-domain rather than the regulatory N-domain, and in patient myocardium it raised rather than lowered Ca2+ sensitivity, so the mouse models the mechanism the human variant does not exhibit. No G159D or E135A knock-in mouse has been reported. Claims about CMD1Z pathophysiology sourced from this model are marked MODEL_ORGANISM in this entry and should be read as support for the desensitization hypothesis group, not as genotype-matched evidence.

Proposed experiments

Genotype-matched TNNC1 knock-in mouse

tnnc1_genotype_matched_knockin_mouse

Generate a G159D or E135A knock-in mouse and test whether it reproduces the dilated phenotype and, specifically, the loss of beta-adrenergic myofilament responsiveness observed in human tissue.

Decision criterion

Reproduction of the dilated phenotype together with a blunted myofilament PKA response would validate the mouse route for the human alleles; a normal or hypertrophic phenotype would confine the D73N result to the engineered allele.

Patient-derived TNNC1 iPSC-cardiomyocytes with isogenic controls

tnnc1_patient_ipsc_cardiomyocytes_isogenic

Derive induced pluripotent stem cell cardiomyocytes from TNNC1 variant carriers, with isogenic CRISPR-corrected controls, to obtain a human in vitro system that retains native post-translational modification and can be assayed for contractility, calcium handling, and beta-adrenergic response.

Decision criterion

Concordance between iPSC-cardiomyocyte and explanted-myocardium measurements would establish the iPSC system as the human-relevant assay in place of the mouse.

Show evidence (2 references)

PMID:26379556 SUPPORT Model Organism

"we generated knock-in mice carrying a D73N mutation (not known to be associated with heart disease in human patients) in cTnC"

The model's own authors state that the modeled allele is not a human disease variant, which is the mismatch this discussion records.

PMID:19808376 SUPPORT Human Clinical

"Maximal Ca(2+)-activated force was similar in cTnC G159D and donor myocytes, but the Ca(2+) sensitivity of cTnC G159D myocytes was higher (EC(50) G159D/donor=0.60)."

Shows the direction of the human G159D effect is opposite to the desensitizing lesion engineered into the mouse, sharpening the mismatch from a formal to a mechanistic one.

Should therapy for TNNC1 dilated cardiomyopathy aim to restore myofilament calcium sensitivity, and if so, how should the direction of correction be chosen for a given variant?

KNOWLEDGE GAP OPEN tnnc1_calcium_sensitizer_therapeutic_direction

Attached to

pathophysiology#Altered Myofilament Calcium Sensitivity pathophysiology#Uncoupling of Troponin Phosphorylation from Calcium Sensitivity

Troponin C is an unusually attractive drug target because it is the Ca2+ sensor itself, and engineered TnC constructs have been shown to correct abnormal thin-filament Ca2+ sensitivity in both directions, restoring actomyosin ATPase activity and force generation in skinned trabeculae. But no such agent exists for patients, and the direction of correction is genotype-dependent in a way that is not currently predictable: TNNC1 variants desensitize (Y5H, M103I, D132N, E135A), sensitize (D145E, and G159D in native myocardium), or leave steady-state sensitivity unchanged while slowing activation (G159D in reconstituted fibres). A variant-agnostic calcium sensitizer could therefore help one CMD1Z patient and harm another. The gap is twofold: no myofilament-directed therapy has reached TNNC1 patients, and no validated assay exists for assigning an individual variant to a correction direction.

Proposed experiments

Standardized human variant-triage assay for TNNC1

tnnc1_standardized_human_variant_triage_assay

Build a standardized human cTnC-depleted myocardium assay that reports both steady-state Ca2+ sensitivity and PKA responsiveness for any candidate TNNC1 variant, and validate it against variants with known clinical phenotypes.

Decision criterion

The assay is usable for triage if its two readouts separate variants with known dilated from known hypertrophic clinical phenotypes.

Direction-specific pharmacology across a TNNC1 variant panel

tnnc1_direction_specific_pharmacology_panel

Test whether calcium sensitizers and myofilament-directed agents produce genotype-dependent, direction-specific effects across a panel of desensitizing and sensitizing TNNC1 variants in the same preparation.

Decision criterion

If a sensitizer corrects desensitizing variants but worsens sensitizing ones, myofilament therapy in TNNC1 disease must be genotype-gated rather than applied to CMD1Z as a class.

Show evidence (2 references)

PMID:22511780 SUPPORT In Vitro

"Rationally engineered TnC constructs corrected the abnormal Ca(2+) sensitivities of the thin filament, reconstituted actomyosin ATPase activity, and force generation in skinned trabeculae."

Establishes proof of principle that resetting thin-filament Ca2+ sensitivity is achievable, which is what makes the unanswered direction-of-correction question actionable rather than academic.

PMID:36158814 SUPPORT Other

"With mounting evidence that thin filament cardiomyopathies occur through a distinct mechanism, there is need for therapies targeting the unique, underlying mechanisms tailored for each patient depending on a given mutation."

States the per-variant tailoring requirement that constitutes the knowledge gap. Evidence source is OTHER because this is a review.

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Pathophysiology

9

Cardiac Troponin C Variant and Thin-Filament Regulatory Defect

TNNC1 encodes cardiac troponin C, an 18-kDa four-EF-hand protein and the calcium sensor of the cardiac thin filament. Its structural C-domain carries two high-affinity sites permanently occupied by Ca2+ or Mg2+ and anchors cTnC to the rest of the troponin complex; its regulatory N-domain carries a single low-affinity site that is largely empty at diastolic Ca2+ and, on binding Ca2+, opens to capture the troponin I switch region and release troponin I's inhibitory segments from actin. Disease-associated missense variants are scattered across both domains — G159D and E135A in the C-terminal structural region, Y5H and G34R in or near the N-terminal regulatory region, M103I, D132N, D145E and I148V elsewhere — and none abolishes the protein. Instead they retune this switch: altering troponin I and troponin T binding, reducing alpha-helical content, and changing the equilibrium between the "active" and "dormant" orientations of the regulatory domain. Because the same gene also produces hypertrophic and restrictive phenotypes, the direction of the functional perturbation, not its presence, determines the clinical phenotype.

Slowed activation-kinetics model Thin-filament calcium-desensitization model Troponin-phosphorylation uncoupling model

Cardiomyocyte CL:0000746

TNNC1 hgnc:11943

Regulation of cardiac muscle contraction GO:0055117 ⚠ ABNORMAL

calcium ion binding GO:0005509 ⚠ ABNORMAL troponin T binding GO:0031014 ⚠ ABNORMAL

Myocardium UBERON:0002349

Downstream

Altered Myofilament Calcium Sensitivity

Uncoupling of Troponin Phosphorylation from Calcium Sensitivity

Slowed Rate of Thin-Filament Activation

Show evidence (5 references)

PMID:26232335 SUPPORT Other

"The structural C-domain (cCTnC) contains two high affinity calcium-binding sites that are always occupied by Ca(2+) or Mg(2+) under physiologic conditions, stabilizing an open conformation that remains anchored to the rest of the troponin complex."

Establishes the two-domain architecture of cardiac troponin C whose perturbation is the primary lesion of this disorder. Evidence source is OTHER because this is a structure-function review.

PMID:26232335 SUPPORT Other

"During muscle activation, calcium binding to cNTnC favors an open conformation that binds to the switch region of troponin I, removing adjacent inhibitory regions of troponin I from actin and allowing muscle contraction to proceed."

Describes the normal Ca2+-triggered switch that TNNC1 variants retune.

PMID:15542288 SUPPORT Human Clinical

"Cardiac troponin C was identified as a novel DCM gene."

The founding CMD1Z observation establishing TNNC1 as a dilated cardiomyopathy gene.

+ 2 more references

Altered Myofilament Calcium Sensitivity

Most DCM-associated thin-filament variants shift the force-pCa relationship rightward, so more Ca2+ is required for the same force and the sarcomere is hypocontractile at physiological systolic Ca2+. Among TNNC1 variants this is documented for Y5H and M103I (decreased Ca2+ sensitivity of force development in skinned fibres), for D132N in the compound-heterozygous sibling pair, and for E135A in reconstituted human cardiac muscle. The shift is small in absolute terms — of the order of 0.1 pCa units for E135A — but it is applied to every beat over a lifetime. Because troponin is also the major Ca2+ buffer of the myocyte cytosol, an altered thin-filament Ca2+ affinity feeds back onto the Ca2+ transient itself and hence onto Ca2+-sensitive remodeling signaling. The direction is not universal: D145E sensitizes, and in explanted G159D myocardium Ca2+ sensitivity was higher than donor tissue, which is why this node is curated under a hypothesis group rather than as settled fact.

Thin-filament calcium-desensitization model

Cardiomyocyte CL:0000746

Regulation of cardiac muscle cell contraction GO:0086004 ↓ DECREASED Cellular response to calcium ion GO:0071277 ⚠ ABNORMAL

Downstream

Impaired Cardiomyocyte Contractile Performance

Show evidence (4 references)

PMID:21832052 SUPPORT In Vitro

"Functional studies using the recombinant human mutant cTnC proteins reconstituted into porcine papillary skinned fibers showed decreased Ca(2+) sensitivity of force development (Y5H and M103I)."

Direct measurement of reduced myofilament Ca2+ sensitivity for two DCM-associated TNNC1 variants.

PMID:32038292 SUPPORT In Vitro

"In contrast, incorporation of 50% WT/50% D132N, which had not been previously reported, decreased Ca2+ sensitivity of isometric force."

Extends the desensitization finding to the D132N allele of the compound-heterozygous sibling pair.

PMID:17932326 SUPPORT In Vitro

"Because troponin is the major Ca(2+) buffer in the cardiomyocyte sarcoplasm, we suggest that Ca(2+) affinity changes caused by cardiomyopathy mutant proteins may directly affect the Ca(2+) transient and hence Ca(2+)-sensitive disease state remodeling pathways in vivo."

Supplies the mechanistic bridge from a thin-filament Ca2+-affinity change to Ca2+-dependent remodeling signaling, the route to the downstream node.

+ 1 more reference

Uncoupling of Troponin Phosphorylation from Calcium Sensitivity

Beta-adrenergic stimulation drives PKA phosphorylation of troponin I at Ser23/24, which desensitizes the myofilament to Ca2+ and speeds relaxation; this is the principal route by which sympathetic drive supplies inotropic and lusitropic reserve. Several TNNC1 variants sever this link. In troponin extracted from an explanted G159D heart, dephosphorylating troponin I no longer produced the large Ca2+-sensitivity shift seen with wild-type troponin; reconstituted human cardiac muscle carrying E135A showed no myofilament response to PKA at all; and in skinned fibres Y5H and I148V diminished, and M103I abolished, the effect of PKA phosphorylation on Ca2+ sensitivity. NMR work provides a structural correlate: DCM-associated cTnC substitutions and troponin I phosphomimetics both destabilize the "active" orientation of the regulatory domain, suggesting mutation and phosphorylation act on the same conformational equilibrium — so a mutation that has already shifted it leaves phosphorylation nothing to do. The functional consequence is a ventricle with no contractile reserve under sympathetic load.

Troponin-phosphorylation uncoupling model

Cardiomyocyte CL:0000746

Adrenergic receptor signaling pathway GO:0071875 ↓ DECREASED Regulation of cardiac muscle contraction GO:0055117 ⚠ ABNORMAL

calcium ion binding GO:0005509 ⚠ ABNORMAL

Downstream

Impaired Cardiomyocyte Contractile Performance

Neurohormonal Activation A myofilament that cannot respond to beta-adrenergic stimulation forces escalating sympathetic drive to maintain output, but the intermediate steps linking myofilament unresponsiveness to systemic neurohormonal activation have not been measured in TNNC1 carriers.

Show evidence (4 references)

PMID:19808376 SUPPORT Human Clinical

"In addition, the cTnC G159D mutation blunted the change in Ca(2+) sensitivity when TnI was dephosphorylated."

The core uncoupling observation, made in troponin from patient myocardium.

PMID:21832052 SUPPORT In Vitro

"Furthermore, the cTnC mutants diminished (Y5H and I148V) or abolished (M103I) the effects of PKA phosphorylation on Ca(2+) sensitivity."

Shows the uncoupling is not private to G159D but recurs across three further DCM-associated TNNC1 variants.

PMID:17577574 SUPPORT In Vitro

"The increased force production of the muscle fibres caused by this phosphomimic was significantly depressed."

Reconstituted-fibre confirmation that G159D suppresses the contractile gain normally produced by PKA phosphorylation of troponin I.

+ 1 more reference

Slowed Rate of Thin-Filament Activation

An alternative kinetic lesion: G159D troponin incorporated into skinned fibres left both the Ca2+ sensitivity and the cooperativity of force generation intact but halved the rate at which force developed after a caged-Ca2+ flash. Systole is time-limited, so a sarcomere that switches on at half rate delivers less force within the ejection period even when its steady-state force-pCa curve is normal — a mechanism invisible to the equilibrium assays on which the canonical model rests.

Slowed activation-kinetics model

Cardiomyocyte CL:0000746

Cardiac muscle contraction GO:0060048 ↓ DECREASED

Downstream

Impaired Cardiomyocyte Contractile Performance

Show evidence (1 reference)

PMID:17021793 SUPPORT In Vitro

"In vivo, this mutation may cause both a slowing of force generation and reduction in total systolic force."

States the predicted in vivo consequence of the halved activation rate, which is the content of this node.

Impaired Cardiomyocyte Contractile Performance

The convergence point of the three mechanistic models. Whether the mutant thin filament is desensitized to Ca2+, unable to respond to beta-adrenergic phosphorylation, or simply slow to switch on, the cardiomyocyte delivers less force per beat and less reserve under load. Because thin-filament cardiomyopathy dysregulates sarcomeric Ca2+ handling rather than the motor itself, its pathomechanism is held to be distinct from thick-filament (myosin) disease, and it is clinically associated with a heavier heart-failure and arrhythmia burden.

Cardiomyocyte CL:0000746

Cardiac muscle contraction GO:0060048 ↓ DECREASED

Myocardium UBERON:0002349

Downstream

Neurohormonal Activation

Adverse Ventricular Remodeling

Show evidence (2 references)

PMID:36158814 SUPPORT Other

"There is significant evidence that thin filament mutations contribute to dysregulation of Ca2+ within the sarcomere and may have a distinct pathomechanism of disease from cardiomyopathy associated with thick filament mutations."

Frames the shared thin-filament Ca2+-dysregulation pathomechanism that this convergence node represents. Evidence source is OTHER because this is a review.

PMID:26379556 SUPPORT Model Organism

"Compared to wild-type mice, heterozygous knock-in mice carrying the D73N mutation exhibited a substantially decreased Ca(2+) sensitivity of force development in skinned ventricular trabeculae."

In vivo demonstration that a cTnC regulatory-domain lesion degrades force development in intact myocardium, though with an engineered rather than a patient TNNC1 allele.

Neurohormonal Activation

Falling stroke volume activates the sympathetic nervous system and the renin-angiotensin-aldosterone system, which sustain perfusion in the short term but drive hypertrophy, fibrosis, and chamber dilation over time. This amplifier is not TNNC1-specific — it is the shared engine of the cardiomyopathy remodeling module — but it carries particular weight in this disorder because the myofilament itself is unresponsive to beta-adrenergic stimulation, so escalating sympathetic drive extracts no inotropic benefit while still exacting its remodeling cost. It is also the target of every available therapy for CMD1Z.

Cardiomyocyte CL:0000746 Cardiac fibroblast CL:0002548

Adrenergic receptor signaling pathway GO:0071875 ↑ INCREASED

Downstream

Adverse Ventricular Remodeling

Show evidence (2 references)

PMID:31073128 SUPPORT Other

"As DCM eventually leads to impaired contractility, standard approaches to prevent or treat heart failure are the first-line treatment for patients with DCM."

Shared module evidence that the dilated cardiomyopathy process culminates in impaired contractility managed with neurohormonal heart-failure therapy. Evidence source is OTHER because this is a review.

PMID:26379556 SUPPORT Model Organism

"Thus, knock-in mice developed pathological features similar to those observed in human patients with dilated cardiomyopathy (DCM)."

Supports the progression from a cTnC lesion to the full DCM phenotype in vivo. PARTIAL because the study does not measure neurohormonal activation directly, and the allele is not a human CMD1Z variant.

Adverse Ventricular Remodeling

Chronic underperformance plus neurohormonal drive remodels the ventricle: chamber dimensions increase, walls thin, the sphere-like geometry raises wall stress by Laplace's law, and interstitial fibrosis accumulates. In the cTnC knock-in model this appears as increased left ventricular dimensions with thinner walls and a rising heart-weight to body-weight ratio; in patients it is the echocardiographic and cardiac-MRI substrate of the diagnosis.

Cardiomyocyte CL:0000746 Cardiac fibroblast CL:0002548

Cardiac muscle hypertrophy GO:0003300 ⚠ ABNORMAL

Left ventricle UBERON:0002084

Downstream

Left Ventricular Dilation and Systolic Dysfunction

Show evidence (2 references)

PMID:26379556 SUPPORT Model Organism

"Echocardiographic analysis revealed that knock-in mice exhibited increased left ventricular dimensions with thinner walls."

Direct in vivo observation of the dilate-and-thin remodeling geometry downstream of a cTnC lesion.

PMID:31073128 SUPPORT Other

"Echocardiography and other imaging techniques are required to assess ventricular dysfunction and adverse myocardial remodelling, and immunological and histological analyses of an endomyocardial biopsy sample are indicated when inflammation or infection is suspected."

Establishes adverse myocardial remodeling as the assessable tissue-level process in DCM. Evidence source is OTHER because this is a review.

Left Ventricular Dilation and Systolic Dysfunction

The clinical phenotype: left ventricular or biventricular dilation with impaired contraction, not explained by loading conditions or coronary disease. In TNNC1 families it can appear from infancy to the fifth decade, and diastolic dysfunction may accompany or precede overt systolic failure — the E135A pedigree included a carrier with normal ejection fraction but clear diastolic abnormality, and diastolic dysfunction is consistent with the predicted increase in ventricular stiffness from slowed cross-bridge detachment.

Heart contraction GO:0060047 ↓ DECREASED

Left ventricle UBERON:0002084

Downstream

Heart Failure, Ventricular Arrhythmia and Sudden Cardiac Death

Show evidence (3 references)

PMID:31073128 SUPPORT Other

"Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left ventricular or biventricular dilation and impaired contraction that is not explained by abnormal loading conditions (for example, hypertension and valvular heart disease) or coronary artery disease."

Defines the organ-level phenotype this node represents. Evidence source is OTHER because this is a review.

PMID:40671656 SUPPORT Human Clinical

"We identified a multigenerational family carrying the TNNC1-c.404A>C variant with autosomal dominant DCM with both systolic and diastolic dysfunctions."

Documents that the TNNC1 organ-level phenotype includes diastolic as well as systolic dysfunction.

PMID:32038292 SUPPORT Human Clinical

"Notably, right ventricular size and function remained normal throughout."

Bears on whether TNNC1 disease is left-ventricular or biventricular. In the one reported case with the right ventricle explicitly followed, it was spared despite severe progressive left-sided disease, so this node is scoped to left ventricular involvement rather than asserting biventricular dysfunction. PARTIAL because a single case cannot exclude right ventricular involvement in the disorder generally.

Heart Failure, Ventricular Arrhythmia and Sudden Cardiac Death

The terminal phase. In the founding TNNC1/TNNT2 cohort, 21 mutation carriers produced 6 cardiac transplantations, 5 deaths from heart failure, and 4 sudden deaths at a mean age of 29 years, with only 6 remaining stable on medication — a course the authors characterized as severe with complete penetrance and an adverse prognosis. Thin-filament cardiomyopathy more generally carries an increased arrhythmia burden and potentially higher mortality than thick-filament disease. The arrhythmic risk is not merely a late consequence of pump failure: in the E135A family the proband survived a ventricular fibrillation arrest with only moderately depressed ejection fraction.

Regulation of heart rate GO:0002027 ⚠ ABNORMAL

Heart UBERON:0000948

Show evidence (2 references)

PMID:15542288 SUPPORT Human Clinical

"A total of 21 mutation carriers were identified; 6 underwent cardiac transplantation, 5 died of heart failure, and 4 died suddenly at a mean age of 29 years, while 6 remained stable on medication."

Quantifies the outcome distribution — transplantation, heart-failure death, and sudden death — in the founding troponin C/T cohort.

PMID:36158814 SUPPORT Other

"increased morbidity associated with heart failure, increased arrhythmia burden and potentially higher mortality"

Supports the arrhythmia and mortality burden of thin-filament cardiomyopathy as a class. PARTIAL because the claim is made across thin-filament genes rather than for TNNC1 specifically.

⬡

Pathograph

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

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Phenotypes

8

Cardiovascular 7

Dilated Cardiomyopathy OBLIGATE HP:0001644

Show evidence (2 references)

PMID:15542288 SUPPORT Human Clinical

"Cardiac troponin C was identified as a novel DCM gene."

Establishes dilated cardiomyopathy as the phenotype defining the TNNC1-DCM relationship.

CGGV:assertion_6ad71467-74c0-4a7c-932d-c5ca5747e59e-2025-05-30T160000.000Z SUPPORT Other

ClinGen records dilated cardiomyopathy as the TNNC1-associated phenotype with Definitive validity. The OBLIGATE band here is definitional rather than empirical: CMD1Z is the dilated node of the TNNC1 allelic series, so every individual affected by this entity has the dilated phenotype by construction. It is a statement about affected individuals, not about carriers — TNNC1 carriers with normal ventricular function are documented elsewhere in this entry, and carrier penetrance is modeled separately under progression.

Reduced Left Ventricular Ejection Fraction HP:0012664

Show evidence (1 reference)

PMID:40671656 SUPPORT Human Clinical

"One of the proband's sons (IV.4) developed depressed LVEF of 33% at 16 years of age without evidence of scar or fibrosis and with normal ECGs."

A documented reduced ejection fraction in a TNNC1 variant carrier, with the value quantified.

Left Ventricular Diastolic Dysfunction HP:0025168

Show evidence (1 reference)

PMID:40671656 SUPPORT Human Clinical

"Her brother, II.3 had normal LVEF (60%) with blunted E/A ratio of 0.6, E'/A' wave reversal, and biatrial enlargement suggesting diastolic dysfunction."

A TNNC1 carrier with isolated diastolic dysfunction and preserved ejection fraction, showing diastolic involvement can be the presenting abnormality.

Congestive Heart Failure HP:0001635

Show evidence (1 reference)

PMID:15542288 SUPPORT Human Clinical

"6 underwent cardiac transplantation, 5 died of heart failure"

Heart failure was the direct cause of death in a quarter of the troponin mutation carriers in the founding cohort.

Ventricular Arrhythmia HP:0004308

Show evidence (1 reference)

PMID:40671656 SUPPORT Human Clinical

"The proband (III.2) survived sudden cardiac arrest from ventricular fibrillation when she was 38 years old and was found to have a depressed left ventricular ejection fraction (LVEF) of 35-40% with recurrent ventricular tachycardia (VT)."

Documents both ventricular fibrillation and recurrent ventricular tachycardia in a TNNC1 variant carrier.

Sudden Cardiac Death HP:0001645

Show evidence (1 reference)

PMID:15542288 SUPPORT Human Clinical

"4 died suddenly at a mean age of 29 years"

Direct documentation of sudden death, with the age at death, in troponin mutation carriers.

Neonatal and Infantile Lethal Cardiomyopathy Dilated cardiomyopathy HP:0001644

Severity: SEVERE

Show evidence (2 references)

PMID:36814108 SUPPORT Human Clinical

"we report a de novo variant, c.100G>C (p.Gly34Arg) in the TNNC1 gene identified in three siblings with a diagnosis of severe DCM causing infant death for one of the siblings and stillbirth in the other two pregnancies"

Documents the lethal infantile and stillborn extreme of the TNNC1 phenotypic range.

PMID:32038292 SUPPORT Human Clinical

"Here, we report the case of two siblings with severe, early onset DCM who were found to have compound heterozygous variants in TNNC1: p.Asp145Glu (D145E) and p.Asp132Asn (D132N), which were inherited from the parents."

A second early-onset severe presentation, here from a compound-heterozygous rather than a de novo genotype.

Other 1

Left Ventricular Dilatation HP:4000141

Show evidence (2 references)

PMID:26379556 SUPPORT Model Organism

"Echocardiographic analysis revealed that knock-in mice exhibited increased left ventricular dimensions with thinner walls."

Model-organism evidence for the dilate-and-thin geometry produced by a cTnC lesion. PARTIAL because the allele is an engineered desensitizing variant rather than a human CMD1Z variant.

PMID:31073128 SUPPORT Other

"Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left ventricular or biventricular dilation and impaired contraction"

Ventricular dilation is definitional for the disease of which CMD1Z is a genetic form. Evidence source is OTHER because this is a review.

🧬

Genetic Associations

1

TNNC1 Pathogenic Variants (Pathogenic Variants)

Gene: TNNC1 hgnc:11943 relationship_type: CAUSATIVE

Autosomal Dominant

Show evidence (5 references)

CGGV:assertion_6ad71467-74c0-4a7c-932d-c5ca5747e59e-2025-05-30T160000.000Z SUPPORT Other

ClinGen Dilated Cardiomyopathy GCEP classifies the TNNC1-DCM gene-disease relationship as Definitive under SOP10.

PMID:33947203 SUPPORT Human Clinical

"Twelve genes (23%) from 8 gene ontologies were classified as having definitive (BAG3, DES, FLNC, LMNA, MYH7, PLN, RBM20, SCN5A, TNNC1, TNNT2, TTN) or strong (DSP) evidence."

The ClinGen DCM gene curation places TNNC1 in the definitive-evidence tier, independently of the later gene-validity assertion.

PMID:31983221 SUPPORT Human Clinical

"Variants in MYH7, LMNA, BAG3, TNNT2, TNNC1, PLN, ACTC1, NEXN, TPM1, and VCL were significantly enriched in specific patient subsets"

Case-control rare-variant burden analysis across 2538 DCM patients confirms a statistically robust TNNC1 excess, independent of candidate-gene reporting bias.

+ 2 more references

Variants (5)

TNNC1 Gly159Asp

Gene: TNNC1 hgnc:11943

c.476G>A, p.Gly159Asp. The founding CMD1Z variant, identified in a large kindred with 100% penetrance and severe disease, and by far the most functionally studied TNNC1 allele — characterized in skinned fibres, in reconstituted thin filaments, by NMR, and in explanted patient myocardium. Its functional signature is a blunted response to troponin phosphorylation and a halved activation rate rather than the canonical Ca2+ desensitization.

Show evidence (1 reference)

PMID:19808376 SUPPORT Human Clinical

"We studied the Ca(2+)-regulatory properties of myocytes and troponin extracted from the explanted heart of a patient with inherited dilated cardiomyopathy due to the cTnC G159D mutation."

Confirms G159D as an inherited-DCM-causing TNNC1 variant carried by a patient who reached transplantation.

TNNC1 Glu135Ala

Gene: TNNC1 hgnc:11943

c.404A>C, p.Glu135Ala. A variant in the G helix just before the fourth EF hand, at a residue 99% conserved across 230 vertebrate species; segregates with autosomal dominant DCM plus diastolic dysfunction and ventricular arrhythmia across a multigenerational family, and abolishes the myofilament response to PKA phosphorylation in reconstituted human cardiac muscle.

Show evidence (1 reference)

PMID:40671656 SUPPORT Human Clinical

"We identified a multigenerational family carrying the TNNC1-c.404A>C variant with autosomal dominant DCM with both systolic and diastolic dysfunctions."

Segregation evidence for the c.404A>C (E135A) variant in a multigenerational DCM pedigree.

TNNC1 Tyr5His, Met103Ile, Asp145Glu and Ile148Val

Gene: TNNC1 hgnc:11943

Four rare variants identified in DCM probands and characterized together. Y5H and M103I decreased the Ca2+ sensitivity of force development; Y5H and I148V diminished, and M103I abolished, the effect of PKA phosphorylation; all except I148V reduced alpha-helical content by circular dichroism. D145E has also been reported in hypertrophic cardiomyopathy, and in its original DCM proband co-occurred with an MYBPC3 variant, so its assignment to the dilated phenotype is not secure.

Show evidence (1 reference)

PMID:21832052 SUPPORT Human Clinical

"Here, we report the clinical, genetic, and functional characterization of four TNNC1 rare variants (Y5H, M103I, D145E, and I148V), all previously reported by us in association with DCM"

Names the four variants of this group and their reported association with dilated cardiomyopathy.

TNNC1 Asp132Asn (compound heterozygous with Asp145Glu)

Gene: TNNC1 hgnc:11943

p.Asp132Asn, inherited in trans with p.Asp145Glu in two siblings with severe early-onset DCM — a rare compound-heterozygous rather than classic dominant genotype. In reconstituted cardiac muscle preparations D132N decreased and D145E increased Ca2+ sensitivity, and the two together mirrored wild type, so the biallelic mechanism is not a simple sum of the single-allele effects.

Show evidence (1 reference)

PMID:32038292 SUPPORT Human Clinical

"Here, we report the case of two siblings with severe, early onset DCM who were found to have compound heterozygous variants in TNNC1: p.Asp145Glu (D145E) and p.Asp132Asn (D132N), which were inherited from the parents."

Documents the compound-heterozygous D132N/D145E genotype and its severe early-onset phenotype.

TNNC1 Gly34Arg

Gene: TNNC1 hgnc:11943

c.100G>C, p.Gly34Arg. A de novo variant recurring in three siblings — one infant death and two stillbirths — implicating parental germline mosaicism. Marks the lethal perinatal extreme of the TNNC1 phenotype.

Show evidence (1 reference)

PMID:36814108 SUPPORT Human Clinical

"we report a de novo variant, c.100G>C (p.Gly34Arg) in the TNNC1 gene identified in three siblings with a diagnosis of severe DCM causing infant death for one of the siblings and stillbirth in the other two pregnancies"

Primary report of the G34R de novo variant and its perinatal-lethal phenotype.

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Medical Actions

6

Guideline-Directed Heart Failure Pharmacotherapy

Action: Pharmacotherapy NCIT:C15986

Agent: angiotensin receptor-neprilysin inhibitor (sacubitril/valsartan) NCIT:C190796 ACE inhibitor (alternative to ARNI) NCIT:C247 beta-blocker NCIT:C29576 mineralocorticoid receptor antagonist (spironolactone as the class exemplar) NCIT:C840 SGLT2 inhibitor NCIT:C98083

Standard heart-failure therapy for left ventricular systolic dysfunction — the four contemporary HFrEF pillars: an angiotensin receptor-neprilysin inhibitor (or an ACE inhibitor / angiotensin receptor blocker where ARNI is not tolerated), a beta-blocker, a mineralocorticoid receptor antagonist, and an SGLT2 inhibitor — targeting the neurohormonal amplifier of adverse remodeling. There is no TNNC1-specific disease-modifying therapy, so management is the generic DCM regimen. Note the mechanistic tension worth recording for this genotype: several TNNC1 variants abolish the myofilament response to PKA-mediated (beta-adrenergic) phosphorylation, so the myofilament substrate that beta-blockade normally protects is already unresponsive; whether this alters the benefit of beta-blockade in TNNC1 carriers has not been studied.

Mechanism Target:

INHIBITS Neurohormonal Activation — Neurohormonal blockade interrupts the maladaptive amplifier between the primary thin-filament lesion and adverse ventricular remodeling.

Show evidence (2 references)

PMID:31073128 SUPPORT Other

"As DCM eventually leads to impaired contractility, standard approaches to prevent or treat heart failure are the first-line treatment for patients with DCM."

Establishes standard heart-failure therapy as first-line management for dilated cardiomyopathy, of which CMD1Z is a genetic form. Evidence source is OTHER because this is a review.

PMID:36158814 SUPPORT Other

"None of these therapies directly address the underlying sarcomeric dysfunction associated with thin-filament mutations."

Records the therapeutic gap: the available regimen treats the downstream neurohormonal amplifier, not the myofilament lesion. PARTIAL because it is a statement of what the therapy does not do.

Implantable Cardioverter Defibrillator

Action: implantable cardioverter-defibrillator placement Ontology label: Implantable Cardioverter-Defibrillator Placement NCIT:C80435

Device therapy for primary or secondary prevention of sudden cardiac death. Particularly relevant in CMD1Z because sudden arrhythmic death occurred at a mean age of 29 years in the founding cohort and because ventricular fibrillation has been the presenting event in a TNNC1 carrier with only moderately reduced ejection fraction.

Show evidence (2 references)

PMID:40671656 SUPPORT Human Clinical

"She was subsequently diagnosed with nonischemic DCM with class I diastolic dysfunction by echocardiogram and had an implantable cardioverter-defibrillator (ICD) placed."

Documents ICD implantation in a TNNC1 variant carrier after a resuscitated ventricular fibrillation arrest.

PMID:31073128 SUPPORT Other

"Cardiac resynchronization therapy and implantable cardioverter-defibrillators may be required to prevent life-threatening arrhythmias."

Establishes device therapy for arrhythmic protection as part of standard DCM management. Evidence source is OTHER because this is a review.

Cardiac Resynchronization Therapy

Action: cardiac resynchronization therapy Ontology label: Cardiac Resynchronization Therapy NCIT:C80436

Biventricular pacing for carriers with persistent systolic dysfunction and a significant intraventricular conduction delay, correcting the mechanical dyssynchrony that compounds an already underperforming ventricle. Indication follows general heart-failure criteria; no TNNC1-specific selection rule exists, and the thin-filament lesion itself is untouched by resynchronization.

Show evidence (1 reference)

PMID:31073128 SUPPORT Other

"Cardiac resynchronization therapy and implantable cardioverter-defibrillators may be required to prevent life-threatening arrhythmias."

Names cardiac resynchronization therapy alongside defibrillator therapy as part of standard dilated cardiomyopathy device management. Evidence source is OTHER because this is a review.

Mechanical Circulatory Support

Action: left ventricular assist device insertion Ontology label: Left Ventricular Assist Device Insertion NCIT:C172327

Durable left ventricular assist device support for carriers refractory to medical therapy, used as a bridge to transplantation or as destination therapy. It is the escalation step between guideline-directed pharmacotherapy and transplantation, and is particularly relevant in this disorder because the founding cohort reached transplantation or death in the majority of carriers.

Show evidence (1 reference)

PMID:28190577 SUPPORT Other

"Patients who are refractory to medical therapy might benefit from mechanical circulatory support and heart transplantation."

Establishes mechanical circulatory support as the escalation option for medically refractory dilated cardiomyopathy, of which CMD1Z is a genetic form. Evidence source is OTHER because this is a seminar review.

Cascade Genetic Testing and Counseling

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

Predictive TNNC1 testing and cardiac surveillance of first-degree relatives. Counseling must address two features peculiar to this gene: onset spans infancy to the fifth decade so a normal echocardiogram in adulthood does not clear a carrier's children, and many TNNC1 variants arise de novo — with at least one documented instance of germline mosaicism causing recurrent perinatal loss — so an apparently negative parental test does not guarantee a low recurrence risk.

Show evidence (3 references)

PMID:20301486 SUPPORT Other

"Provide a basic view of genetic risk assessment of at-risk asymptomatic relatives of a proband with DCM to inform cardiac surveillance and allow early detection and treatment of DCM to improve long-term outcome."

The GeneReviews DCM overview frames genetic risk assessment of at-risk asymptomatic relatives, with cardiac surveillance for early detection, as precisely this intervention. Evidence source is OTHER because GeneReviews is an expert-authored review resource.

PMID:36814108 SUPPORT Human Clinical

"The identification of the same de novo variant in all affected siblings is suggestive of germline mosaicism in this family."

The specific counseling hazard: germline mosaicism produces recurrence risk that parental testing does not capture.

PMID:15542288 SUPPORT Human Clinical

"The data suggest that mutation analysis of the troponin complex in DCM patients may prove valuable in early identification of individuals with an adverse prognosis and a high risk of premature death."

The founding argument for cascade genotyping in troponin-gene DCM.

Heart Transplantation

Action: Organ transplantation Ontology label: Organ Transplantation NCIT:C15289

Advanced therapy for end-stage heart failure, with mechanical circulatory support as a bridge. Transplantation is not a rare tail event in this disorder: 6 of 21 carriers in the founding troponin cohort were transplanted, and the explanted CMD1Z myocardium obtained at transplantation has been the source of the only human-tissue mechanical studies of this disease.

Show evidence (2 references)

PMID:15542288 SUPPORT Human Clinical

"A total of 21 mutation carriers were identified; 6 underwent cardiac transplantation, 5 died of heart failure, and 4 died suddenly at a mean age of 29 years, while 6 remained stable on medication."

Quantifies transplantation as an outcome in the founding troponin mutation cohort, with the denominator explicit: 6 of 21 carriers were transplanted.

PMID:19808376 SUPPORT Human Clinical

"We studied the Ca(2+)-regulatory properties of myocytes and troponin extracted from the explanted heart of a patient with inherited dilated cardiomyopathy due to the cTnC G159D mutation."

Documents that a G159D carrier progressed to transplantation. PARTIAL because this is incidental evidence of transplant use rather than an efficacy study.

🔬

Diagnosis

4

Echocardiography

First-line imaging. Left ventricular dimensions and ejection fraction establish the dilated phenotype, and diastolic indices (E/A ratio, tissue-Doppler E'/A', atrial size) capture the filling abnormality that can be the earliest finding in a TNNC1 carrier. Echocardiography is also the surveillance modality for genotype-positive, phenotype-negative relatives identified by cascade testing.

echocardiography NCIT:C16525

Show evidence (2 references)

PMID:31073128 SUPPORT Other

"Echocardiography and other imaging techniques are required to assess ventricular dysfunction and adverse myocardial remodelling, and immunological and histological analyses of an endomyocardial biopsy sample are indicated when inflammation or infection is suspected."

Establishes echocardiography as the required modality for assessing ventricular dysfunction and remodeling in DCM. Evidence source is OTHER because this is a review.

PMID:40671656 SUPPORT Human Clinical

"She was subsequently diagnosed with nonischemic DCM with class I diastolic dysfunction by echocardiogram and had an implantable cardioverter-defibrillator (ICD) placed."

Worked example in a TNNC1 family: echocardiography simultaneously established the dilated phenotype and graded the diastolic abnormality.

Cardiac Magnetic Resonance Imaging with Late Gadolinium Enhancement

Cardiac MRI quantifies chamber volumes and function more reproducibly than echocardiography and, with late gadolinium enhancement, distinguishes replacement fibrosis from its absence. In the E135A family it specifically excluded scar in an adolescent carrier with a reduced ejection fraction, which is informative because absence of late enhancement argues against a burnt-out myocarditic or ischemic cause and supports a primary myofilament disease.

cardiac magnetic resonance imaging with late gadolinium enhancement NCIT:C16809

Show evidence (1 reference)

PMID:40671656 SUPPORT Human Clinical

"Then, cardiac MRI was performed specifically to evaluate for fibrosis/scar. The dilation and reduced EF were confirmed and furthermore, there was no evidence of scar by gadolinium enhancement and no delayed enhancement of the myocardium."

Documents the specific diagnostic role of cardiac MRI in a TNNC1 carrier: confirming the dilated phenotype while excluding scar.

Cardiomyopathy Multigene Panel Sequencing

The confirmatory test is molecular. TNNC1 is a definitive-evidence DCM gene and is included on clinically curated cardiomyopathy panels alongside TTN, LMNA, MYH7, TNNT2, BAG3, DES, FLNC, PLN, RBM20 and SCN5A; exome or genome sequencing is a reasonable second tier. Two interpretive caveats are specific to this gene: most reported TNNC1 variants are de novo, so familial segregation evidence is often unavailable, and TNNC1 variants also cause hypertrophic and restrictive disease, so a variant must be read against the observed phenotype rather than assumed to be a CMD1Z allele.

cardiomyopathy multigene panel sequencing NCIT:C15709

Show evidence (2 references)

PMID:33947203 SUPPORT Human Clinical

"Clinical genetic testing panels include most high-evidence genes; however, genes lacking robust evidence are also commonly included."

The ClinGen DCM panel's finding about panel composition, which is the interpretive framework this diagnostic entry applies; TNNC1 falls in the high-evidence set.

PMID:40671656 SUPPORT Human Clinical

"Given the family history of DCM, gene panel testing for cardiomyopathy and arrhythmia associated genes was performed for the proband (III.2) with cascade testing performed in II.2, II.3, IV.2, and IV.4."

Worked example of the panel-then-cascade testing pathway in a TNNC1 family.

Exclusion of Loading Conditions and Coronary Disease

DCM is definitionally a diagnosis of exclusion: the dilation and systolic impairment must not be explained by hypertension, valvular disease, or coronary artery disease, and the acquired causes (myocarditis, alcohol and other toxins, the peripartum state, tachyarrhythmia, endocrine and autoimmune disease) must be considered before a genetic label is applied. A pathogenic TNNC1 genotype does not remove this step.

Show evidence (2 references)

PMID:31073128 SUPPORT Other

"Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left ventricular or biventricular dilation and impaired contraction that is not explained by abnormal loading conditions (for example, hypertension and valvular heart disease) or coronary artery disease."

States the exclusion criteria that define the DCM diagnosis. Evidence source is OTHER because this is a review.

PMID:20301486 SUPPORT Other

"Provide the evaluation strategy of a proband with nonsyndromic DCM"

The GeneReviews DCM overview exists to supply this proband evaluation strategy, of which exclusion of non-genetic causes is the first step. Evidence source is OTHER because GeneReviews is an expert-authored review.

📈

Progression

3

Genotype-positive, phenotype-negative

A relative identified by cascade testing may carry the TNNC1 variant with normal imaging. Penetrance in the founding G159D kindred was 100%, but that is a single-pedigree figure; population data on DCM-gene carriers put combined clinical plus subclinical penetrance at no more than about 30%. Surveillance rather than treatment is the correct posture at this stage, with attention to diastolic indices since these can be the first abnormality in TNNC1 families.

Show evidence (2 references)

PMID:15542288 SUPPORT Human Clinical

"The prevalence of TNNC1/TNNT2 mutations in familial DCM was 5% with a penetrance of 100%."

The complete-penetrance figure for the founding cohort. PARTIAL because it derives from ascertained mutation-positive families and cannot be generalized to unselected carriers.

PMID:35708014 SUPPORT Human Clinical

"The combined clinical/subclinical penetrance was ≤30% with all 3 variant filtering strategies."

Quantifies incomplete penetrance across DCM genes in an unselected population cohort, the counterweight to the founding pedigree's 100% figure. PARTIAL because the estimate is across DCM genes rather than TNNC1-specific.

Manifest dilated cardiomyopathy

Once the phenotype declares itself the course is progressive rather than episodic, with dilation, falling ejection fraction, and symptomatic heart failure. Onset spans infancy to the fifth decade, so the phase is not tied to a life stage.

Show evidence (1 reference)

PMID:15542288 SUPPORT Human Clinical

"The disease expression associated with TNNC1 and TNNT2 mutations was severe with complete penetrance."

Characterizes the manifest phase as severe in troponin-gene DCM.

End-stage heart failure, transplantation or sudden death

The terminal phase. In the founding cohort a majority of the 21 troponin mutation carriers reached transplantation or death; sudden arrhythmic death occurred at a mean age of 29 years, and can precede end-stage pump failure.

Show evidence (1 reference)

PMID:15542288 SUPPORT Human Clinical

"The data suggest that mutation analysis of the troponin complex in DCM patients may prove valuable in early identification of individuals with an adverse prognosis and a high risk of premature death."

States the adverse-prognosis conclusion that defines this phase and motivates early genotyping.

📊

Prevalence

2

Worldwide

Unknown Not yet documented

No population-based prevalence estimate exists for the TNNC1-specific form of dilated cardiomyopathy. TNNC1 is a definitive but numerically minor DCM gene: in a consecutive cohort of 235 idiopathic DCM patients, TNNC1 and TNNT2 variants together accounted for 5% of familial DCM, and TNNC1 rare variants were found in 1.3% of a separate 312-proband DCM cohort.

Show evidence (1 reference)

PMID:15542288 SUPPORT Human Clinical

"The prevalence of TNNC1/TNNT2 mutations in familial DCM was 5% with a penetrance of 100%."

Gives the mutation frequency of the troponin C/T pair within a familial DCM cohort. PARTIAL because it is a cohort mutation frequency, not a population prevalence, and it does not separate TNNC1 from TNNT2.

Idiopathic or familial DCM probands (US resequencing cohort, n=312)

Unknown Not yet documented

TNNC1 rare variants were identified in 4 of 312 probands (1.3%) in a bidirectional-resequencing study of five sarcomere genes, the best available estimate of the TNNC1 share of genotyped DCM.

Show evidence (1 reference)

PMID:20215591 SUPPORT Human Clinical

"4 TNNC1 (cardiac troponin C) in 4 (1.3%)"

Quantifies the fraction of DCM probands carrying a TNNC1 rare variant in a systematically resequenced cohort.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Dilated Cardiomyopathy 1Z:

Ischemic and other acquired dilated cardiomyopathy

Overlapping Features Coronary artery disease, hypertension, valvular disease, tachyarrhythmia, alcohol and other cardiotoxins, and endocrine or autoimmune disease all produce a dilated, hypocontractile ventricle and must be excluded before a genetic diagnosis is made.

Distinguishing Features

Regional (coronary-territory) wall-motion abnormality or an ischemic late-gadolinium-enhancement pattern favors ischemic cardiomyopathy.
Absent family history plus an identified exposure or loading condition, with recovery after its removal, favors an acquired cause.

Show evidence (1 reference)

PMID:31073128 SUPPORT Other

"Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left ventricular or biventricular dilation and impaired contraction that is not explained by abnormal loading conditions (for example, hypertension and valvular heart disease) or coronary artery disease."

The definition itself enumerates the acquired conditions that must be excluded. Evidence source is OTHER because this is a review.

TTN-truncating and other high-evidence genetic dilated cardiomyopathy

Overlapping Features TTN truncating variants are the single most common identifiable genetic cause of DCM, and LMNA, BAG3, FLNC, RBM20, DES, PLN, SCN5A, MYH7 and TNNT2 account for most of the remainder. These are clinically indistinguishable from CMD1Z at the bedside; the discrimination is molecular.

Distinguishing Features

LMNA and DES disease is typically preceded by conduction-system disease and atrioventricular block; TNNC1 disease is not characteristically conduction-first.
Only a multigene panel or broader sequencing separates the genotypes; imaging and clinical course overlap substantially.

Show evidence (1 reference)

PMID:31983221 SUPPORT Human Clinical

"Truncating variants in TTN and DSP were associated with DCM in all comparisons."

Identifies the highest-yield alternative genotypes that a TNNC1 diagnosis must be distinguished from.

🧫

Experimental Models

4

cTnC D73N knock-in mouse OTHER

Heterozygous knock-in mice carrying an engineered D73N substitution in the regulatory N-domain of cardiac troponin C, designed to reduce thin-filament Ca2+ sensitivity by accelerating Ca2+ dissociation. The mice show decreased Ca2+ sensitivity of force development in skinned trabeculae, increased left ventricular dimensions with thinner walls, dramatically reduced ejection fraction and fractional shortening, prolonged QRS and QT intervals, and ventricular myocytes that fail to respond to beta-adrenergic stimulation, with a median survival of 12 weeks. It is the only in vivo model of a cTnC-driven dilated phenotype, and it establishes sufficiency of N-domain Ca2+ desensitization — but the allele is explicitly not a human disease variant (see the HUMAN_MODEL_MISMATCH discussion).

Organism

house mouse NCBITaxon:10090

Publication

PMID:26379556

Show evidence (1 reference)

PMID:26379556 SUPPORT Model Organism

"Kaplan-Meier survival analysis revealed that median survival time for knock-in mice was 12 weeks."

Documents the model's defining survival phenotype, the headline readout of this experimental system.

cTnC-depleted human donor cardiac muscle preparations reconstituted with recombinant mutant cTnC OTHER

Permeabilized myocardial strips from a non-failing human donor heart are depleted of endogenous cTnC with CDTA and reconstituted with a 50:50 mixture of recombinant wild-type and mutant cTnC to mimic the heterozygous state, then assayed for steady-state isometric force versus pCa, cooperativity, sinusoidal stiffness, rate of tension redevelopment, and the response to PKA incubation. This is the closest available human-tissue system for testing a candidate TNNC1 variant and was the system in which E135A was shown to abolish the PKA response. The porcine papillary equivalent was used for the earlier Y5H/M103I/D145E/I148V and D132N characterizations.

Organism

human NCBITaxon:9606

Cell source

Permeabilized left ventricular strips from a non-failing human donor heart

Publication

PMID:40671656

Show evidence (1 reference)

PMID:40671656 SUPPORT In Vitro

"cTnC-depleted donor human cardiac muscle preparations were reconstituted with recombinant exogenous human cTnC-E135A. Steady-state isometric force and crossbridge kinetics were measured before and after PKA incubation."

Describes the preparation and the measurements this model system supports.

Explanted CMD1Z (G159D) human myocardium OTHER

Myocytes and troponin extracted from the explanted heart of a G159D carrier at transplantation, studied by skinned-myocyte force-pCa measurement, in vitro motility assay of reconstituted thin filaments, and mass spectrometry of troponin phosphorylation state. The only study of native CMD1Z myocardium, and the source of the phosphorylation-uncoupling model — notably, it contradicted the direction of the Ca2+-sensitivity change predicted by prior reconstituted systems.

Organism

human NCBITaxon:9606

Cell source

Explanted left ventricular myocardium from a patient with the TNNC1 G159D variant

Publication

PMID:19808376

Show evidence (1 reference)

PMID:19808376 SUPPORT Human Clinical

"In vitro, these mutations decrease Ca(2+) sensitivity and cross-bridge turnover rate, but the mutations have not been investigated in human tissue."

States what makes this model system unique: it is the first study of these thin-filament mutations in native human tissue rather than reconstituted systems.

Xenopus tropicalis TNNC1 CRISPR/Cas9 knockout OTHER

CRISPR/Cas9 knockout of tnnc1 in Xenopus tropicalis produced a tadpole cardiac phenotype consistent with dilated cardiomyopathy. Its documented limitation is instructive: the authors could not rescue the tadpole hearts with either wild-type or patient-variant human cTnC, so the model could not be used to test variant-specific effects and the study fell back on reconstituted mammalian muscle preparations.

Organism

western clawed frog NCBITaxon:8364

Publication

PMID:32038292

Show evidence (1 reference)

PMID:32038292 SUPPORT Model Organism

"We began our investigation with CRISPR/Cas9 knockout of TNNC1 in Xenopus tropicalis, which resulted in a cardiac phenotype in tadpoles consistent with DCM."

Establishes the knockout model and its DCM-consistent tadpole phenotype.

{ }

Source YAML

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name: Dilated Cardiomyopathy 1Z
creation_date: "2026-08-02T00:00:00Z"
synonyms:
- CMD1Z
- TNNC1 familial isolated dilated cardiomyopathy
- dilated cardiomyopathy type 1Z
- cardiomyopathy, dilated, 1Z
- TNNC1-related dilated cardiomyopathy
description: >-
  Dilated cardiomyopathy 1Z (CMD1Z) is the TNNC1-related form of familial
  isolated dilated cardiomyopathy. TNNC1 encodes cardiac troponin C (cTnC), the
  calcium-binding subunit of the thin-filament troponin complex and the calcium
  sensor of the cardiac sarcomere: its regulatory N-terminal domain binds Ca2+
  at a single low-affinity site, opens, and captures the switch region of
  troponin I, which lifts troponin I's inhibitory segments off actin and permits
  cross-bridge cycling. Heterozygous missense variants in TNNC1 do not abolish
  the protein; they retune this Ca2+-regulated switch. TNNC1 was established as
  a dilated cardiomyopathy gene by Mogensen and colleagues in 2004, who found
  the founding p.Gly159Asp (G159D) variant in a large kindred with complete
  penetrance and an unusually severe course, and ClinGen's Dilated
  Cardiomyopathy Gene Curation Expert Panel now classifies the TNNC1-DCM
  relationship as Definitive with autosomal dominant inheritance. How a cTnC
  variant produces a dilated rather than a hypertrophic phenotype is genuinely
  unsettled and is curated here as three competing mechanistic models: the
  canonical thin-filament calcium-desensitization model (DCM variants lower, and
  hypertrophic variants raise, myofilament Ca2+ sensitivity), a
  phosphorylation-uncoupling model derived from explanted human myocardium (in
  which G159D raised Ca2+ sensitivity but severed the normal link between
  troponin I phosphorylation and Ca2+ sensitivity, blunting beta-adrenergic
  reserve), and a kinetic model in which the primary defect is a halved rate of
  force activation with no change in the steady-state force-pCa relationship.
  Downstream the three converge on impaired cardiomyocyte contractile
  performance, neurohormonal activation, adverse ventricular remodeling,
  progressive left ventricular dilation with systolic dysfunction, and heart
  failure with ventricular arrhythmia and sudden cardiac death. TNNC1 is a
  pleiotropic locus: different substitutions in the same small protein cause
  hypertrophic (CMH13) and restrictive cardiomyopathy, and ClinGen classifies
  the TNNC1-hypertrophic relationship as Definitive in parallel. Disease is
  typically autosomal dominant, but rare compound-heterozygous and de novo
  (including germline-mosaic) presentations with severe infantile disease are
  reported.
category: Genetic
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
disease_term:
  preferred_term: dilated cardiomyopathy 1Z
  term:
    id: MONDO:0012745
    label: dilated cardiomyopathy 1Z
parents:
- Dilated Cardiomyopathy
- Genetic Disorder
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    No population-based prevalence estimate exists for the TNNC1-specific form of
    dilated cardiomyopathy. TNNC1 is a definitive but numerically minor DCM gene:
    in a consecutive cohort of 235 idiopathic DCM patients, TNNC1 and TNNT2
    variants together accounted for 5% of familial DCM, and TNNC1 rare variants
    were found in 1.3% of a separate 312-proband DCM cohort.
  evidence:
  - reference: PMID:15542288
    reference_title: Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prevalence of TNNC1/TNNT2 mutations in familial DCM was 5% with a
      penetrance of 100%.
    explanation: >-
      Gives the mutation frequency of the troponin C/T pair within a familial DCM
      cohort. PARTIAL because it is a cohort mutation frequency, not a population
      prevalence, and it does not separate TNNC1 from TNNT2.
- population: Idiopathic or familial DCM probands (US resequencing cohort, n=312)
  measure_type: UNKNOWN
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    TNNC1 rare variants were identified in 4 of 312 probands (1.3%) in a
    bidirectional-resequencing study of five sarcomere genes, the best available
    estimate of the TNNC1 share of genotyped DCM.
  evidence:
  - reference: PMID:20215591
    reference_title: Coding sequence rare variants identified in MYBPC3, MYH6, TPM1, TNNC1, and TNNI3 from 312 patients with familial or idiopathic dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      4 TNNC1 (cardiac troponin C) in 4 (1.3%)
    explanation: >-
      Quantifies the fraction of DCM probands carrying a TNNC1 rare variant in a
      systematically resequenced cohort.
inheritance:
- name: Autosomal Dominant
  description: >-
    CMD1Z is transmitted as an autosomal dominant trait: a single heterozygous
    missense allele in TNNC1 is sufficient, and the mutant protein is expressed
    approximately equimolar with wild-type cTnC in patient myocardium, consistent
    with an altered-function (dominant-negative) rather than haploinsufficiency
    mechanism. ClinGen's Dilated Cardiomyopathy Gene Curation Expert Panel records
    autosomal dominant inheritance with Definitive clinical validity.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: CGGV:assertion_6ad71467-74c0-4a7c-932d-c5ca5747e59e-2025-05-30T160000.000Z
    reference_title: TNNC1 / dilated cardiomyopathy (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      TNNC1 | HGNC:11943 | dilated cardiomyopathy | MONDO:0005021 | AD |
      Definitive
    explanation: >-
      ClinGen Dilated Cardiomyopathy GCEP records autosomal dominant inheritance
      for the TNNC1 gene-disease relationship, classified Definitive.
  - reference: PMID:40671656
    reference_title: Cardiac Troponin C E135A Variant Impairs Myofilament Response to PKA Phosphorylation and Is Associated With Autosomal Dominant Dilated Cardiomyopathy With Diastolic Dysfunction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a multigenerational family carrying the TNNC1-c.404A>C
      variant with autosomal dominant DCM with both systolic and diastolic
      dysfunctions.
    explanation: >-
      A contemporary multigenerational pedigree demonstrating autosomal dominant
      segregation of a TNNC1 variant with DCM.
  - reference: PMID:19808376
    reference_title: Functional analysis of a unique troponin c mutation, GLY159ASP, that causes familial dilated cardiomyopathy, studied in explanted heart muscle.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mass spectroscopy showed that the mutant cTnC was expressed approximately
      equimolar with wild-type cTnC.
    explanation: >-
      Direct measurement in patient myocardium that both alleles are expressed,
      supporting a dominant altered-function mechanism rather than
      haploinsufficiency.
- name: De Novo and Germline Mosaic
  description: >-
    A substantial share of reported TNNC1 variants are de novo rather than
    inherited, which is why segregation data are scarce for this gene. Recurrence
    of the same de novo TNNC1 variant in three siblings with lethal infantile DCM
    established germline mosaicism as a recurrence mechanism relevant to
    reproductive counseling.
  evidence:
  - reference: PMID:40671656
    reference_title: Cardiac Troponin C E135A Variant Impairs Myofilament Response to PKA Phosphorylation and Is Associated With Autosomal Dominant Dilated Cardiomyopathy With Diastolic Dysfunction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Unlike other sarcomere genes, most reports of TNNC1 variants lack
      segregation or pedigree data, partly because the majority of the variants
      described, to date, have been reported as de novo.
    explanation: >-
      Documents that de novo occurrence is the norm rather than the exception for
      reported TNNC1 variants.
  - reference: PMID:36814108
    reference_title: "A novel variant of TNNC1 associated with severe dilated cardiomyopathy causing infant mortality and stillbirth: a case of germline mosaicism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The identification of the same de novo variant in all affected siblings is
      suggestive of germline mosaicism in this family.
    explanation: >-
      Establishes germline mosaicism as a recurrence mechanism for an apparently
      de novo TNNC1 variant.
mechanistic_hypotheses:
- hypothesis_group_id: tnnc1_calcium_desensitization_model
  hypothesis_label: Thin-filament calcium-desensitization model
  status: CANONICAL
  description: >-
    The canonical model of thin-filament cardiomyopathy holds that DCM-causing
    troponin and tropomyosin variants lower the Ca2+ sensitivity of the
    myofilament while hypertrophic variants raise it, so that at any given
    systolic Ca2+ transient the mutant sarcomere generates less force. Applied to
    TNNC1, a variant that destabilizes the regulatory N-domain, accelerates Ca2+
    dissociation, or perturbs the cTnC structure reduces the fraction of thin
    filament switched on per beat, producing a hypocontractile ventricle that
    dilates. This model is directly supported for the TNNC1 variants Y5H and
    M103I, for the compound-heterozygous D132N allele, for the E135A pedigree
    variant, and by a knock-in mouse in which engineered Ca2+ desensitization of
    the cTnC N-domain alone was sufficient to cause early-onset DCM.
  evidence:
  - reference: PMID:17932326
    reference_title: Dilated and hypertrophic cardiomyopathy mutations in troponin and alpha-tropomyosin have opposing effects on the calcium affinity of cardiac thin filaments.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In vitro functional assays show that, in general, the presence of dilated
      cardiomyopathy mutations decreases the Ca(2+) sensitivity of contractility,
      whereas HCM mutations increase it.
    explanation: >-
      States the canonical opposing-Ca2+-sensitivity paradigm that this hypothesis
      group encodes, and the study then confirms it at the level of thin-filament
      Ca2+ affinity.
  - reference: PMID:26379556
    reference_title: Knock-in mice harboring a Ca(2+) desensitizing mutation in cardiac troponin C develop early onset dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In conclusion, our results suggest that decreasing Ca(2+) sensitivity of the
      regulatory N-domain of cTnC is sufficient to trigger the development of DCM.
    explanation: >-
      Provides the sufficiency argument for the desensitization model in vivo,
      though with an engineered rather than a patient-derived TNNC1 allele (see
      the HUMAN_MODEL_MISMATCH discussion).
- hypothesis_group_id: tnnc1_phosphorylation_uncoupling_model
  hypothesis_label: Troponin-phosphorylation uncoupling model
  status: ALTERNATIVE
  description: >-
    A competing model, derived principally from explanted human myocardium rather
    than reconstituted systems, holds that the pathogenic lesion is not the
    absolute level of myofilament Ca2+ sensitivity but the loss of its regulation.
    Normally, PKA phosphorylation of troponin I at Ser23/24 during beta-adrenergic
    stimulation desensitizes the myofilament to Ca2+, accelerating relaxation and
    supplying inotropic and lusitropic reserve; dephosphorylation reverses this. In
    myocardium from a G159D carrier the mutant troponin abolished that
    phosphorylation-dependent shift, and the same abolition is seen for the E135A
    pedigree variant in reconstituted human cardiac muscle and for M103I in
    skinned fibres. Under this model the ventricle fails because it cannot respond
    to sympathetic drive, not because its resting Ca2+ sensitivity is low — indeed
    in the G159D explanted heart Ca2+ sensitivity was higher than donor myocardium,
    the opposite of the canonical prediction.
  evidence:
  - reference: PMID:19808376
    reference_title: Functional analysis of a unique troponin c mutation, GLY159ASP, that causes familial dilated cardiomyopathy, studied in explanted heart muscle.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We propose that uncoupling of the relationship between phosphorylation and
      Ca(2+) sensitivity could be the cause of the dilated cardiomyopathy
      phenotype.
    explanation: >-
      The primary statement of this alternative model, made from patient
      myocardium carrying the founding CMD1Z variant.
  - reference: PMID:40671656
    reference_title: Cardiac Troponin C E135A Variant Impairs Myofilament Response to PKA Phosphorylation and Is Associated With Autosomal Dominant Dilated Cardiomyopathy With Diastolic Dysfunction.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Using reconstituted human cardiac muscle preparations, we showed that the
      cTnC-E135A abolishes the myofilament response to PKA-mediated
      phosphorylation.
    explanation: >-
      Independent replication of the uncoupling mechanism in human cardiac muscle
      preparations with a different, segregating TNNC1 variant.
  - reference: PMID:17577574
    reference_title: DCM troponin C mutant Gly159Asp blunts the response to troponin phosphorylation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We conclude that this DCM mutant significantly blunts the contractile
      response to phosphorylation and this novel mechanism may contribute to its
      pathogenic effect.
    explanation: >-
      Reconstituted-fibre demonstration of the same blunted phosphorylation
      response for G159D, using PKA and PKC phosphomimetics.
- hypothesis_group_id: tnnc1_activation_kinetics_model
  hypothesis_label: Slowed activation-kinetics model
  status: EMERGING
  description: >-
    A third, kinetic account proposes that the primary defect of at least some
    TNNC1 variants lies in the rate at which the thin filament switches on rather
    than in the steady-state force-pCa relationship. G159D troponin incorporated
    into skinned fibres left Ca2+ sensitivity and cooperativity unchanged but
    halved the activation rate, which in an intact beating ventricle would truncate
    systolic force development within the available ejection time. A related
    kinetic reading comes from in silico modeling of the E135A variant, where a
    slowed Ca2+ off-rate and slowed myosin detachment predict increased ventricular
    stiffness alongside reduced ejection fraction. The model is EMERGING because
    the kinetic parameters have been measured in reconstituted and computational
    systems rather than in beating human myocardium.
  evidence:
  - reference: PMID:17021793
    reference_title: Functional effects of the DCM mutant Gly159Asp troponin C in skinned muscle fibres.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Gly159Asp TnC had no significant effect on either the Ca(2+) sensitivity or
      cooperativity of force generation when compared to wild type. However, the
      mutation caused a highly significant (ca. 50%) decrease in the rate of
      activation.
    explanation: >-
      Establishes a kinetic (rate-of-activation) defect that is explicitly
      dissociated from the steady-state Ca2+ sensitivity change the canonical
      model predicts.
  - reference: PMID:17021793
    reference_title: Functional effects of the DCM mutant Gly159Asp troponin C in skinned muscle fibres.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This represents a novel mechanism by which a cardiomyopathy-causing mutation
      can affect contractility.
    explanation: >-
      The authors themselves frame the kinetic defect as a mechanism distinct from
      the established Ca2+-sensitivity paradigm, which is why this group is
      curated separately rather than folded into the canonical model.
  - reference: PMID:40671656
    reference_title: Cardiac Troponin C E135A Variant Impairs Myofilament Response to PKA Phosphorylation and Is Associated With Autosomal Dominant Dilated Cardiomyopathy With Diastolic Dysfunction.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      in silico mathematical modeling showed that this variant affects crossbridge
      kinetics by decreasing both Ca2+ kOFF-rate constant and myosin detachment
      rate, which could result in increased ventricular stiffness and reduced
      ejection fraction
    explanation: >-
      Computational support for a kinetic route to contractile failure. PARTIAL
      because the kinetic parameters are modeled rather than measured, and because
      the direction of the rate change differs from the G159D activation-rate
      finding.
pathophysiology:
- name: Cardiac Troponin C Variant and Thin-Filament Regulatory Defect
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    TNNC1 encodes cardiac troponin C, an 18-kDa four-EF-hand protein and the
    calcium sensor of the cardiac thin filament. Its structural C-domain carries
    two high-affinity sites permanently occupied by Ca2+ or Mg2+ and anchors cTnC
    to the rest of the troponin complex; its regulatory N-domain carries a single
    low-affinity site that is largely empty at diastolic Ca2+ and, on binding
    Ca2+, opens to capture the troponin I switch region and release troponin I's
    inhibitory segments from actin. Disease-associated missense variants are
    scattered across both domains — G159D and E135A in the C-terminal structural
    region, Y5H and G34R in or near the N-terminal regulatory region, M103I,
    D132N, D145E and I148V elsewhere — and none abolishes the protein. Instead
    they retune this switch: altering troponin I and troponin T binding, reducing
    alpha-helical content, and changing the equilibrium between the "active" and
    "dormant" orientations of the regulatory domain. Because the same gene also
    produces hypertrophic and restrictive phenotypes, the direction of the
    functional perturbation, not its presence, determines the clinical phenotype.
  genes:
  - preferred_term: TNNC1
    term:
      id: hgnc:11943
      label: TNNC1
  molecular_functions:
  - preferred_term: calcium ion binding
    term:
      id: GO:0005509
      label: calcium ion binding
    modifier: ABNORMAL
  - preferred_term: troponin T binding
    term:
      id: GO:0031014
      label: troponin T binding
    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: Regulation of cardiac muscle contraction
    term:
      id: GO:0055117
      label: regulation of cardiac muscle contraction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:26232335
    reference_title: "Structure and function of cardiac troponin C (TNNC1): Implications for heart failure, cardiomyopathies, and troponin modulating drugs."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The structural C-domain (cCTnC) contains two high affinity calcium-binding
      sites that are always occupied by Ca(2+) or Mg(2+) under physiologic
      conditions, stabilizing an open conformation that remains anchored to the
      rest of the troponin complex.
    explanation: >-
      Establishes the two-domain architecture of cardiac troponin C whose
      perturbation is the primary lesion of this disorder. Evidence source is
      OTHER because this is a structure-function review.
  - reference: PMID:26232335
    reference_title: "Structure and function of cardiac troponin C (TNNC1): Implications for heart failure, cardiomyopathies, and troponin modulating drugs."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      During muscle activation, calcium binding to cNTnC favors an open
      conformation that binds to the switch region of troponin I, removing
      adjacent inhibitory regions of troponin I from actin and allowing muscle
      contraction to proceed.
    explanation: >-
      Describes the normal Ca2+-triggered switch that TNNC1 variants retune.
  - reference: PMID:15542288
    reference_title: Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiac troponin C was identified as a novel DCM gene.
    explanation: >-
      The founding CMD1Z observation establishing TNNC1 as a dilated
      cardiomyopathy gene.
  - reference: PMID:15542288
    reference_title: Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Functional studies showed significant impairment of mutated troponin
      interaction compared with wild-type control, indicating an altered
      regulation of myocardial contractility.
    explanation: >-
      Frames the primary defect as altered regulatory protein-protein interaction
      within the troponin complex rather than loss of the protein.
  - reference: PMID:21832052
    reference_title: Functional characterization of TNNC1 rare variants identified in dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These results suggest that each mutation alters the function/ability of the
      myofilament to bind Ca(2+) as a result of modifications in cTnC structure.
    explanation: >-
      Links the structural perturbation of cTnC to altered myofilament Ca2+
      handling across four DCM-associated TNNC1 variants.
  downstream:
  - target: Altered Myofilament Calcium Sensitivity
    causal_link_type: DIRECT
    hypothesis_groups:
    - tnnc1_calcium_desensitization_model
  - target: Uncoupling of Troponin Phosphorylation from Calcium Sensitivity
    causal_link_type: DIRECT
    hypothesis_groups:
    - tnnc1_phosphorylation_uncoupling_model
  - target: Slowed Rate of Thin-Filament Activation
    causal_link_type: DIRECT
    hypothesis_groups:
    - tnnc1_activation_kinetics_model

- name: Altered Myofilament Calcium Sensitivity
  biological_scale: MOLECULAR
  role: amplifier
  description: >-
    Most DCM-associated thin-filament variants shift the force-pCa relationship
    rightward, so more Ca2+ is required for the same force and the sarcomere is
    hypocontractile at physiological systolic Ca2+. Among TNNC1 variants this is
    documented for Y5H and M103I (decreased Ca2+ sensitivity of force development
    in skinned fibres), for D132N in the compound-heterozygous sibling pair, and
    for E135A in reconstituted human cardiac muscle. The shift is small in
    absolute terms — of the order of 0.1 pCa units for E135A — but it is applied
    to every beat over a lifetime. Because troponin is also the major Ca2+ buffer
    of the myocyte cytosol, an altered thin-filament Ca2+ affinity feeds back onto
    the Ca2+ transient itself and hence onto Ca2+-sensitive remodeling signaling.
    The direction is not universal: D145E sensitizes, and in explanted G159D
    myocardium Ca2+ sensitivity was higher than donor tissue, which is why this
    node is curated under a hypothesis group rather than as settled fact.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Regulation of cardiac muscle cell contraction
    term:
      id: GO:0086004
      label: regulation of cardiac muscle cell contraction
    modifier: DECREASED
  - preferred_term: Cellular response to calcium ion
    term:
      id: GO:0071277
      label: cellular response to calcium ion
    modifier: ABNORMAL
  evidence:
  - reference: PMID:21832052
    reference_title: Functional characterization of TNNC1 rare variants identified in dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Functional studies using the recombinant human mutant cTnC proteins
      reconstituted into porcine papillary skinned fibers showed decreased Ca(2+)
      sensitivity of force development (Y5H and M103I).
    explanation: >-
      Direct measurement of reduced myofilament Ca2+ sensitivity for two
      DCM-associated TNNC1 variants.
  - reference: PMID:32038292
    reference_title: Familial Dilated Cardiomyopathy Associated With a Novel Combination of Compound Heterozygous TNNC1 Variants.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In contrast, incorporation of 50% WT/50% D132N, which had not been
      previously reported, decreased Ca2+ sensitivity of isometric force.
    explanation: >-
      Extends the desensitization finding to the D132N allele of the
      compound-heterozygous sibling pair.
  - reference: PMID:17932326
    reference_title: Dilated and hypertrophic cardiomyopathy mutations in troponin and alpha-tropomyosin have opposing effects on the calcium affinity of cardiac thin filaments.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Because troponin is the major Ca(2+) buffer in the cardiomyocyte sarcoplasm,
      we suggest that Ca(2+) affinity changes caused by cardiomyopathy mutant
      proteins may directly affect the Ca(2+) transient and hence Ca(2+)-sensitive
      disease state remodeling pathways in vivo.
    explanation: >-
      Supplies the mechanistic bridge from a thin-filament Ca2+-affinity change to
      Ca2+-dependent remodeling signaling, the route to the downstream node.
  - reference: PMID:19808376
    reference_title: Functional analysis of a unique troponin c mutation, GLY159ASP, that causes familial dilated cardiomyopathy, studied in explanted heart muscle.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Maximal Ca(2+)-activated force was similar in cTnC G159D and donor myocytes,
      but the Ca(2+) sensitivity of cTnC G159D myocytes was higher (EC(50)
      G159D/donor=0.60).
    explanation: >-
      Counter-evidence, retained deliberately: in patient myocardium the founding
      CMD1Z variant raised rather than lowered Ca2+ sensitivity, so the
      desensitization node does not hold for every TNNC1 genotype.
  downstream:
  - target: Impaired Cardiomyocyte Contractile Performance
    causal_link_type: DIRECT
    hypothesis_groups:
    - tnnc1_calcium_desensitization_model

- name: Uncoupling of Troponin Phosphorylation from Calcium Sensitivity
  biological_scale: MOLECULAR
  role: amplifier
  description: >-
    Beta-adrenergic stimulation drives PKA phosphorylation of troponin I at
    Ser23/24, which desensitizes the myofilament to Ca2+ and speeds relaxation;
    this is the principal route by which sympathetic drive supplies inotropic and
    lusitropic reserve. Several TNNC1 variants sever this link. In troponin
    extracted from an explanted G159D heart, dephosphorylating troponin I no
    longer produced the large Ca2+-sensitivity shift seen with wild-type troponin;
    reconstituted human cardiac muscle carrying E135A showed no myofilament
    response to PKA at all; and in skinned fibres Y5H and I148V diminished, and
    M103I abolished, the effect of PKA phosphorylation on Ca2+ sensitivity. NMR
    work provides a structural correlate: DCM-associated cTnC substitutions and
    troponin I phosphomimetics both destabilize the "active" orientation of the
    regulatory domain, suggesting mutation and phosphorylation act on the same
    conformational equilibrium — so a mutation that has already shifted it leaves
    phosphorylation nothing to do. The functional consequence is a ventricle with
    no contractile reserve under sympathetic load.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  molecular_functions:
  - preferred_term: calcium ion binding
    term:
      id: GO:0005509
      label: calcium ion binding
    modifier: ABNORMAL
  biological_processes:
  - preferred_term: Adrenergic receptor signaling pathway
    term:
      id: GO:0071875
      label: adrenergic receptor signaling pathway
    modifier: DECREASED
  - preferred_term: Regulation of cardiac muscle contraction
    term:
      id: GO:0055117
      label: regulation of cardiac muscle contraction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:19808376
    reference_title: Functional analysis of a unique troponin c mutation, GLY159ASP, that causes familial dilated cardiomyopathy, studied in explanted heart muscle.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, the cTnC G159D mutation blunted the change in Ca(2+)
      sensitivity when TnI was dephosphorylated.
    explanation: >-
      The core uncoupling observation, made in troponin from patient myocardium.
  - reference: PMID:21832052
    reference_title: Functional characterization of TNNC1 rare variants identified in dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Furthermore, the cTnC mutants diminished (Y5H and I148V) or abolished
      (M103I) the effects of PKA phosphorylation on Ca(2+) sensitivity.
    explanation: >-
      Shows the uncoupling is not private to G159D but recurs across three further
      DCM-associated TNNC1 variants.
  - reference: PMID:17577574
    reference_title: DCM troponin C mutant Gly159Asp blunts the response to troponin phosphorylation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The increased force production of the muscle fibres caused by this
      phosphomimic was significantly depressed.
    explanation: >-
      Reconstituted-fibre confirmation that G159D suppresses the contractile gain
      normally produced by PKA phosphorylation of troponin I.
  - reference: PMID:33901537
    reference_title: Dilated Cardiomyopathy Mutations and Phosphorylation disrupt the Active Orientation of Cardiac Troponin C.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We propose that the calcium sensitivity of the cardiac troponin complex is
      regulated by an equilibrium between active and dormant orientations, which
      can be shifted through post-translational modifications or DCM-associated
      mutations.
    explanation: >-
      Offers the structural mechanism for why mutation and phosphorylation are not
      independent: both act on the same conformational equilibrium of the
      regulatory domain.
  downstream:
  - target: Impaired Cardiomyocyte Contractile Performance
    causal_link_type: DIRECT
    hypothesis_groups:
    - tnnc1_phosphorylation_uncoupling_model
  - target: Neurohormonal Activation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A myofilament that cannot respond to beta-adrenergic stimulation forces
      escalating sympathetic drive to maintain output, but the intermediate steps
      linking myofilament unresponsiveness to systemic neurohormonal activation
      have not been measured in TNNC1 carriers.
    hypothesis_groups:
    - tnnc1_phosphorylation_uncoupling_model

- name: Slowed Rate of Thin-Filament Activation
  biological_scale: MOLECULAR
  role: amplifier
  description: >-
    An alternative kinetic lesion: G159D troponin incorporated into skinned fibres
    left both the Ca2+ sensitivity and the cooperativity of force generation
    intact but halved the rate at which force developed after a caged-Ca2+ flash.
    Systole is time-limited, so a sarcomere that switches on at half rate delivers
    less force within the ejection period even when its steady-state force-pCa
    curve is normal — a mechanism invisible to the equilibrium assays on which the
    canonical model rests.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Cardiac muscle contraction
    term:
      id: GO:0060048
      label: cardiac muscle contraction
    modifier: DECREASED
  evidence:
  - reference: PMID:17021793
    reference_title: Functional effects of the DCM mutant Gly159Asp troponin C in skinned muscle fibres.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In vivo, this mutation may cause both a slowing of force generation and
      reduction in total systolic force.
    explanation: >-
      States the predicted in vivo consequence of the halved activation rate,
      which is the content of this node.
  downstream:
  - target: Impaired Cardiomyocyte Contractile Performance
    causal_link_type: DIRECT
    hypothesis_groups:
    - tnnc1_activation_kinetics_model

- name: Impaired Cardiomyocyte Contractile Performance
  biological_scale: CELLULAR
  role: central_effector
  description: >-
    The convergence point of the three mechanistic models. Whether the mutant thin
    filament is desensitized to Ca2+, unable to respond to beta-adrenergic
    phosphorylation, or simply slow to switch on, the cardiomyocyte delivers less
    force per beat and less reserve under load. Because thin-filament
    cardiomyopathy dysregulates sarcomeric Ca2+ handling rather than the motor
    itself, its pathomechanism is held to be distinct from thick-filament (myosin)
    disease, and it is clinically associated with a heavier heart-failure and
    arrhythmia burden.
  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: Cardiac muscle contraction
    term:
      id: GO:0060048
      label: cardiac muscle contraction
    modifier: DECREASED
  evidence:
  - reference: PMID:36158814
    reference_title: "Thin filament cardiomyopathies: A review of genetics, disease mechanisms, and emerging therapeutics."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      There is significant evidence that thin filament mutations contribute to
      dysregulation of Ca2+ within the sarcomere and may have a distinct
      pathomechanism of disease from cardiomyopathy associated with thick filament
      mutations.
    explanation: >-
      Frames the shared thin-filament Ca2+-dysregulation pathomechanism that this
      convergence node represents. Evidence source is OTHER because this is a
      review.
  - reference: PMID:26379556
    reference_title: Knock-in mice harboring a Ca(2+) desensitizing mutation in cardiac troponin C develop early onset dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Compared to wild-type mice, heterozygous knock-in mice carrying the D73N
      mutation exhibited a substantially decreased Ca(2+) sensitivity of force
      development in skinned ventricular trabeculae.
    explanation: >-
      In vivo demonstration that a cTnC regulatory-domain lesion degrades force
      development in intact myocardium, though with an engineered rather than a
      patient TNNC1 allele.
  downstream:
  - target: Neurohormonal Activation
    causal_link_type: DIRECT
  - target: Adverse Ventricular Remodeling
    causal_link_type: DIRECT

- name: Neurohormonal Activation
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Neurohormonal Activation"
  biological_scale: ORGANISM
  role: amplifier
  description: >-
    Falling stroke volume activates the sympathetic nervous system and the
    renin-angiotensin-aldosterone system, which sustain perfusion in the short
    term but drive hypertrophy, fibrosis, and chamber dilation over time. This
    amplifier is not TNNC1-specific — it is the shared engine of the
    cardiomyopathy remodeling module — but it carries particular weight in this
    disorder because the myofilament itself is unresponsive to beta-adrenergic
    stimulation, so escalating sympathetic drive extracts no inotropic benefit
    while still exacting its remodeling cost. It is also the target of every
    available therapy for CMD1Z.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: Cardiac fibroblast
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  biological_processes:
  - preferred_term: Adrenergic receptor signaling pathway
    term:
      id: GO:0071875
      label: adrenergic receptor signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:31073128
    reference_title: Dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      As DCM eventually leads to impaired contractility, standard approaches to
      prevent or treat heart failure are the first-line treatment for patients
      with DCM.
    explanation: >-
      Shared module evidence that the dilated cardiomyopathy process culminates in
      impaired contractility managed with neurohormonal heart-failure therapy.
      Evidence source is OTHER because this is a review.
  - reference: PMID:26379556
    reference_title: Knock-in mice harboring a Ca(2+) desensitizing mutation in cardiac troponin C develop early onset dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Thus, knock-in mice developed pathological features similar to those
      observed in human patients with dilated cardiomyopathy (DCM).
    explanation: >-
      Supports the progression from a cTnC lesion to the full DCM phenotype in
      vivo. PARTIAL because the study does not measure neurohormonal activation
      directly, and the allele is not a human CMD1Z variant.
  downstream:
  - target: Adverse Ventricular Remodeling
    causal_link_type: DIRECT

- name: Adverse Ventricular Remodeling
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
  biological_scale: TISSUE
  role: amplifier
  description: >-
    Chronic underperformance plus neurohormonal drive remodels the ventricle:
    chamber dimensions increase, walls thin, the sphere-like geometry raises wall
    stress by Laplace's law, and interstitial fibrosis accumulates. In the cTnC
    knock-in model this appears as increased left ventricular dimensions with
    thinner walls and a rising heart-weight to body-weight ratio; in patients it
    is the echocardiographic and cardiac-MRI substrate of the diagnosis.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: Cardiac fibroblast
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  locations:
  - preferred_term: 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: ABNORMAL
  evidence:
  - reference: PMID:26379556
    reference_title: Knock-in mice harboring a Ca(2+) desensitizing mutation in cardiac troponin C develop early onset dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Echocardiographic analysis revealed that knock-in mice exhibited increased
      left ventricular dimensions with thinner walls.
    explanation: >-
      Direct in vivo observation of the dilate-and-thin remodeling geometry
      downstream of a cTnC lesion.
  - reference: PMID:31073128
    reference_title: Dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Echocardiography and other imaging techniques are required to assess
      ventricular dysfunction and adverse myocardial remodelling, and
      immunological and histological analyses of an endomyocardial biopsy sample
      are indicated when inflammation or infection is suspected.
    explanation: >-
      Establishes adverse myocardial remodeling as the assessable tissue-level
      process in DCM. Evidence source is OTHER because this is a review.
  downstream:
  - target: Left Ventricular Dilation and Systolic Dysfunction
    causal_link_type: DIRECT

- name: Left Ventricular Dilation and Systolic Dysfunction
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Progressive Contractile Dysfunction"
  biological_scale: ORGANISM
  role: consequence
  description: >-
    The clinical phenotype: left ventricular or biventricular dilation with
    impaired contraction, not explained by loading conditions or coronary disease.
    In TNNC1 families it can appear from infancy to the fifth decade, and diastolic
    dysfunction may accompany or precede overt systolic failure — the E135A
    pedigree included a carrier with normal ejection fraction but clear diastolic
    abnormality, and diastolic dysfunction is consistent with the predicted
    increase in ventricular stiffness from slowed cross-bridge detachment.
  locations:
  - preferred_term: Left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  biological_processes:
  - preferred_term: Heart contraction
    term:
      id: GO:0060047
      label: heart contraction
    modifier: DECREASED
  evidence:
  - reference: PMID:31073128
    reference_title: Dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left
      ventricular or biventricular dilation and impaired contraction that is not
      explained by abnormal loading conditions (for example, hypertension and
      valvular heart disease) or coronary artery disease.
    explanation: >-
      Defines the organ-level phenotype this node represents. Evidence source is
      OTHER because this is a review.
  - reference: PMID:40671656
    reference_title: Cardiac Troponin C E135A Variant Impairs Myofilament Response to PKA Phosphorylation and Is Associated With Autosomal Dominant Dilated Cardiomyopathy With Diastolic Dysfunction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a multigenerational family carrying the TNNC1-c.404A>C
      variant with autosomal dominant DCM with both systolic and diastolic
      dysfunctions.
    explanation: >-
      Documents that the TNNC1 organ-level phenotype includes diastolic as well as
      systolic dysfunction.
  - reference: PMID:32038292
    reference_title: Familial Dilated Cardiomyopathy Associated With a Novel Combination of Compound Heterozygous TNNC1 Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Notably, right ventricular size and function remained normal throughout.
    explanation: >-
      Bears on whether TNNC1 disease is left-ventricular or biventricular. In the
      one reported case with the right ventricle explicitly followed, it was spared
      despite severe progressive left-sided disease, so this node is scoped to left
      ventricular involvement rather than asserting biventricular dysfunction.
      PARTIAL because a single case cannot exclude right ventricular involvement in
      the disorder generally.
  downstream:
  - target: Heart Failure, Ventricular Arrhythmia and Sudden Cardiac Death
    causal_link_type: DIRECT

- name: Heart Failure, Ventricular Arrhythmia and Sudden Cardiac Death
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure"
  biological_scale: ORGANISM
  role: outcome
  description: >-
    The terminal phase. In the founding TNNC1/TNNT2 cohort, 21 mutation carriers
    produced 6 cardiac transplantations, 5 deaths from heart failure, and 4 sudden
    deaths at a mean age of 29 years, with only 6 remaining stable on medication —
    a course the authors characterized as severe with complete penetrance and an
    adverse prognosis. Thin-filament cardiomyopathy more generally carries an
    increased arrhythmia burden and potentially higher mortality than
    thick-filament disease. The arrhythmic risk is not merely a late consequence of
    pump failure: in the E135A family the proband survived a ventricular
    fibrillation arrest with only moderately depressed ejection fraction.
  locations:
  - preferred_term: Heart
    term:
      id: UBERON:0000948
      label: heart
  biological_processes:
  - preferred_term: Regulation of heart rate
    term:
      id: GO:0002027
      label: regulation of heart rate
    modifier: ABNORMAL
  evidence:
  - reference: PMID:15542288
    reference_title: Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A total of 21 mutation carriers were identified; 6 underwent cardiac
      transplantation, 5 died of heart failure, and 4 died suddenly at a mean age
      of 29 years, while 6 remained stable on medication.
    explanation: >-
      Quantifies the outcome distribution — transplantation, heart-failure death,
      and sudden death — in the founding troponin C/T cohort.
  - reference: PMID:36158814
    reference_title: "Thin filament cardiomyopathies: A review of genetics, disease mechanisms, and emerging therapeutics."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      increased morbidity associated with heart failure, increased arrhythmia
      burden and potentially higher mortality
    explanation: >-
      Supports the arrhythmia and mortality burden of thin-filament cardiomyopathy
      as a class. PARTIAL because the claim is made across thin-filament genes
      rather than for TNNC1 specifically.
phenotypes:
- category: Cardiovascular
  name: Dilated Cardiomyopathy
  description: >-
    Left ventricular or biventricular dilation with impaired systolic contraction,
    the defining feature of CMD1Z and the phenotype in which TNNC1 was first
    identified as a disease gene.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  evidence:
  - reference: PMID:15542288
    reference_title: Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiac troponin C was identified as a novel DCM gene.
    explanation: >-
      Establishes dilated cardiomyopathy as the phenotype defining the TNNC1-DCM
      relationship.
  - reference: CGGV:assertion_6ad71467-74c0-4a7c-932d-c5ca5747e59e-2025-05-30T160000.000Z
    reference_title: TNNC1 / dilated cardiomyopathy (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      TNNC1 | HGNC:11943 | dilated cardiomyopathy | MONDO:0005021 | AD |
      Definitive
    explanation: >-
      ClinGen records dilated cardiomyopathy as the TNNC1-associated phenotype with
      Definitive validity. The OBLIGATE band here is definitional rather than
      empirical: CMD1Z is the dilated node of the TNNC1 allelic series, so every
      individual affected by this entity has the dilated phenotype by construction.
      It is a statement about affected individuals, not about carriers — TNNC1
      carriers with normal ventricular function are documented elsewhere in this
      entry, and carrier penetrance is modeled separately under progression.
- category: Cardiovascular
  name: Left Ventricular Dilatation
  description: >-
    Increased left ventricular end-diastolic dimension with wall thinning, the
    structural component of the dilated phenotype and the finding that separates it
    from the hypertrophic expression of the same gene.
  phenotype_term:
    preferred_term: Left ventricular dilatation
    term:
      id: HP:4000141
      label: Left ventricular dilatation
  evidence:
  - reference: PMID:26379556
    reference_title: Knock-in mice harboring a Ca(2+) desensitizing mutation in cardiac troponin C develop early onset dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Echocardiographic analysis revealed that knock-in mice exhibited increased
      left ventricular dimensions with thinner walls.
    explanation: >-
      Model-organism evidence for the dilate-and-thin geometry produced by a cTnC
      lesion. PARTIAL because the allele is an engineered desensitizing variant
      rather than a human CMD1Z variant.
  - reference: PMID:31073128
    reference_title: Dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left
      ventricular or biventricular dilation and impaired contraction
    explanation: >-
      Ventricular dilation is definitional for the disease of which CMD1Z is a
      genetic form. Evidence source is OTHER because this is a review.
- category: Cardiovascular
  name: Reduced Left Ventricular Ejection Fraction
  description: >-
    Depressed systolic function on echocardiography or cardiac MRI. In the E135A
    kindred affected members had ejection fractions of 20-40%, including a
    16-year-old with an ejection fraction of 33%.
  phenotype_term:
    preferred_term: Reduced left ventricular ejection fraction
    term:
      id: HP:0012664
      label: Reduced left ventricular ejection fraction
  evidence:
  - reference: PMID:40671656
    reference_title: Cardiac Troponin C E135A Variant Impairs Myofilament Response to PKA Phosphorylation and Is Associated With Autosomal Dominant Dilated Cardiomyopathy With Diastolic Dysfunction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One of the proband's sons (IV.4) developed depressed LVEF of 33% at 16 years
      of age without evidence of scar or fibrosis and with normal ECGs.
    explanation: >-
      A documented reduced ejection fraction in a TNNC1 variant carrier, with the
      value quantified.
- category: Cardiovascular
  name: Left Ventricular Diastolic Dysfunction
  description: >-
    Impaired ventricular filling, which in TNNC1 disease can precede or accompany
    systolic failure and may be the sole abnormality in an early carrier. It is
    mechanistically consistent with the predicted increase in ventricular stiffness
    from slowed Ca2+ dissociation and myosin detachment.
  phenotype_term:
    preferred_term: Left ventricular diastolic dysfunction
    term:
      id: HP:0025168
      label: Left ventricular diastolic dysfunction
  evidence:
  - reference: PMID:40671656
    reference_title: Cardiac Troponin C E135A Variant Impairs Myofilament Response to PKA Phosphorylation and Is Associated With Autosomal Dominant Dilated Cardiomyopathy With Diastolic Dysfunction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Her brother, II.3 had normal LVEF (60%) with blunted E/A ratio of 0.6, E'/A'
      wave reversal, and biatrial enlargement suggesting diastolic dysfunction.
    explanation: >-
      A TNNC1 carrier with isolated diastolic dysfunction and preserved ejection
      fraction, showing diastolic involvement can be the presenting abnormality.
- category: Cardiovascular
  name: Congestive Heart Failure
  description: >-
    Symptomatic pump failure, the usual presenting syndrome and a leading cause of
    death in TNNC1 carriers.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:15542288
    reference_title: Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      6 underwent cardiac transplantation, 5 died of heart failure
    explanation: >-
      Heart failure was the direct cause of death in a quarter of the troponin
      mutation carriers in the founding cohort.
- category: Cardiovascular
  name: Ventricular Arrhythmia
  description: >-
    Ventricular tachycardia and ventricular fibrillation occur in TNNC1 carriers,
    and can appear at ejection fractions that would not by themselves mandate
    device therapy.
  phenotype_term:
    preferred_term: Ventricular arrhythmia
    term:
      id: HP:0004308
      label: Ventricular arrhythmia
  evidence:
  - reference: PMID:40671656
    reference_title: Cardiac Troponin C E135A Variant Impairs Myofilament Response to PKA Phosphorylation and Is Associated With Autosomal Dominant Dilated Cardiomyopathy With Diastolic Dysfunction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The proband (III.2) survived sudden cardiac arrest from ventricular
      fibrillation when she was 38 years old and was found to have a depressed left
      ventricular ejection fraction (LVEF) of 35-40% with recurrent ventricular
      tachycardia (VT).
    explanation: >-
      Documents both ventricular fibrillation and recurrent ventricular tachycardia
      in a TNNC1 variant carrier.
- category: Cardiovascular
  name: Sudden Cardiac Death
  description: >-
    Sudden arrhythmic death, documented in the founding TNNC1/TNNT2 cohort at a
    mean age of 29 years and a principal reason the genotype is treated as
    prognostically informative.
  phenotype_term:
    preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: PMID:15542288
    reference_title: Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      4 died suddenly at a mean age of 29 years
    explanation: >-
      Direct documentation of sudden death, with the age at death, in troponin
      mutation carriers.
- category: Cardiovascular
  name: Neonatal and Infantile Lethal Cardiomyopathy
  description: >-
    At the severe end of the spectrum, de novo and compound-heterozygous TNNC1
    genotypes cause fatal cardiomyopathy in infancy and stillbirth. This
    presentation, rather than the adult-onset familial one, defines the extreme of
    the CMD1Z expressivity range, which spans infancy to the fifth decade.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
    severity: SEVERE
  evidence:
  - reference: PMID:36814108
    reference_title: "A novel variant of TNNC1 associated with severe dilated cardiomyopathy causing infant mortality and stillbirth: a case of germline mosaicism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we report a de novo variant, c.100G>C (p.Gly34Arg) in the TNNC1 gene
      identified in three siblings with a diagnosis of severe DCM causing infant
      death for one of the siblings and stillbirth in the other two pregnancies
    explanation: >-
      Documents the lethal infantile and stillborn extreme of the TNNC1 phenotypic
      range.
  - reference: PMID:32038292
    reference_title: Familial Dilated Cardiomyopathy Associated With a Novel Combination of Compound Heterozygous TNNC1 Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report the case of two siblings with severe, early onset DCM who
      were found to have compound heterozygous variants in TNNC1: p.Asp145Glu
      (D145E) and p.Asp132Asn (D132N), which were inherited from the parents.
    explanation: >-
      A second early-onset severe presentation, here from a compound-heterozygous
      rather than a de novo genotype.
genetic:
- name: TNNC1 Pathogenic Variants
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: TNNC1
    term:
      id: hgnc:11943
      label: TNNC1
  inheritance:
  - name: Autosomal Dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    evidence:
    - reference: CGGV:assertion_6ad71467-74c0-4a7c-932d-c5ca5747e59e-2025-05-30T160000.000Z
      reference_title: TNNC1 / dilated cardiomyopathy (Definitive)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        TNNC1 | HGNC:11943 | dilated cardiomyopathy | MONDO:0005021 | AD |
        Definitive
      explanation: >-
        ClinGen records AD as the mode of inheritance for the TNNC1-DCM
        gene-disease relationship.
  features: >-
    TNNC1 is a small gene encoding a 161-residue protein, and reported
    DCM-associated variants are missense changes distributed across both EF-hand
    domains rather than clustered: G34R and Y5H in or near the N-terminal
    regulatory domain, M103I, D132N, E135A, D145E, I148V and G159D in the
    C-terminal structural region. No truncating or copy-number mechanism is
    established. The gene is pleiotropic — some substitutions (A8V, C84Y, E134D,
    and D145E in some cohorts) produce hypertrophic or restrictive rather than
    dilated disease, and ClinGen classifies both the TNNC1-DCM and the
    TNNC1-hypertrophic relationships as Definitive — so the phenotype cannot be
    predicted from the gene alone. Interpretation is further complicated by the
    scarcity of segregation data: most reported TNNC1 variants are de novo, so
    ClinGen-grade case-level evidence rests on a small number of informative
    pedigrees. ACMG has added TNNC1 to its secondary-findings reporting list.
  variants:
  - name: TNNC1 Gly159Asp
    description: >-
      c.476G>A, p.Gly159Asp. The founding CMD1Z variant, identified in a large
      kindred with 100% penetrance and severe disease, and by far the most
      functionally studied TNNC1 allele — characterized in skinned fibres, in
      reconstituted thin filaments, by NMR, and in explanted patient myocardium.
      Its functional signature is a blunted response to troponin phosphorylation
      and a halved activation rate rather than the canonical Ca2+ desensitization.
    gene:
      preferred_term: TNNC1
      term:
        id: hgnc:11943
        label: TNNC1
    evidence:
    - reference: PMID:19808376
      reference_title: Functional analysis of a unique troponin c mutation, GLY159ASP, that causes familial dilated cardiomyopathy, studied in explanted heart muscle.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
          We studied the Ca(2+)-regulatory properties of myocytes and troponin
          extracted from the explanted heart of a patient with inherited dilated
          cardiomyopathy due to the cTnC G159D mutation.
      explanation: >-
          Confirms G159D as an inherited-DCM-causing TNNC1 variant carried by a patient
          who reached transplantation.
  - name: TNNC1 Glu135Ala
    description: >-
      c.404A>C, p.Glu135Ala. A variant in the G helix just before the fourth EF
      hand, at a residue 99% conserved across 230 vertebrate species; segregates
      with autosomal dominant DCM plus diastolic dysfunction and ventricular
      arrhythmia across a multigenerational family, and abolishes the myofilament
      response to PKA phosphorylation in reconstituted human cardiac muscle.
    gene:
      preferred_term: TNNC1
      term:
        id: hgnc:11943
        label: TNNC1
    evidence:
    - reference: PMID:40671656
      reference_title: Cardiac Troponin C E135A Variant Impairs Myofilament Response to PKA Phosphorylation and Is Associated With Autosomal Dominant Dilated Cardiomyopathy With Diastolic Dysfunction.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
          We identified a multigenerational family carrying the TNNC1-c.404A>C
          variant with autosomal dominant DCM with both systolic and diastolic
          dysfunctions.
      explanation: >-
          Segregation evidence for the c.404A>C (E135A) variant in a multigenerational
          DCM pedigree.
  - name: TNNC1 Tyr5His, Met103Ile, Asp145Glu and Ile148Val
    description: >-
      Four rare variants identified in DCM probands and characterized together.
      Y5H and M103I decreased the Ca2+ sensitivity of force development; Y5H and
      I148V diminished, and M103I abolished, the effect of PKA phosphorylation;
      all except I148V reduced alpha-helical content by circular dichroism. D145E
      has also been reported in hypertrophic cardiomyopathy, and in its original
      DCM proband co-occurred with an MYBPC3 variant, so its assignment to the
      dilated phenotype is not secure.
    gene:
      preferred_term: TNNC1
      term:
        id: hgnc:11943
        label: TNNC1
    evidence:
    - reference: PMID:21832052
      reference_title: Functional characterization of TNNC1 rare variants identified in dilated cardiomyopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
          Here, we report the clinical, genetic, and functional characterization of
          four TNNC1 rare variants (Y5H, M103I, D145E, and I148V), all previously
          reported by us in association with DCM
      explanation: >-
          Names the four variants of this group and their reported association with
          dilated cardiomyopathy.
  - name: TNNC1 Asp132Asn (compound heterozygous with Asp145Glu)
    description: >-
      p.Asp132Asn, inherited in trans with p.Asp145Glu in two siblings with severe
      early-onset DCM — a rare compound-heterozygous rather than classic dominant
      genotype. In reconstituted cardiac muscle preparations D132N decreased and
      D145E increased Ca2+ sensitivity, and the two together mirrored wild type, so
      the biallelic mechanism is not a simple sum of the single-allele effects.
    gene:
      preferred_term: TNNC1
      term:
        id: hgnc:11943
        label: TNNC1
    evidence:
    - reference: PMID:32038292
      reference_title: Familial Dilated Cardiomyopathy Associated With a Novel Combination of Compound Heterozygous TNNC1 Variants.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
          Here, we report the case of two siblings with severe, early onset DCM who
          were found to have compound heterozygous variants in TNNC1: p.Asp145Glu
          (D145E) and p.Asp132Asn (D132N), which were inherited from the parents.
      explanation: >-
          Documents the compound-heterozygous D132N/D145E genotype and its severe
          early-onset phenotype.
  - name: TNNC1 Gly34Arg
    description: >-
      c.100G>C, p.Gly34Arg. A de novo variant recurring in three siblings — one
      infant death and two stillbirths — implicating parental germline mosaicism.
      Marks the lethal perinatal extreme of the TNNC1 phenotype.
    gene:
      preferred_term: TNNC1
      term:
        id: hgnc:11943
        label: TNNC1
    evidence:
    - reference: PMID:36814108
      reference_title: "A novel variant of TNNC1 associated with severe dilated cardiomyopathy causing infant mortality and stillbirth: a case of germline mosaicism."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
          we report a de novo variant, c.100G>C (p.Gly34Arg) in the TNNC1 gene
          identified in three siblings with a diagnosis of severe DCM causing infant
          death for one of the siblings and stillbirth in the other two pregnancies
      explanation: >-
          Primary report of the G34R de novo variant and its perinatal-lethal
          phenotype.
  evidence:
  - reference: CGGV:assertion_6ad71467-74c0-4a7c-932d-c5ca5747e59e-2025-05-30T160000.000Z
    reference_title: TNNC1 / dilated cardiomyopathy (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      TNNC1 | HGNC:11943 | dilated cardiomyopathy | MONDO:0005021 | AD |
      Definitive
    explanation: >-
      ClinGen Dilated Cardiomyopathy GCEP classifies the TNNC1-DCM gene-disease
      relationship as Definitive under SOP10.
  - reference: PMID:33947203
    reference_title: Evidence-Based Assessment of Genes in Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Twelve genes (23%) from 8 gene ontologies were classified as having
      definitive (BAG3, DES, FLNC, LMNA, MYH7, PLN, RBM20, SCN5A, TNNC1, TNNT2,
      TTN) or strong (DSP) evidence.
    explanation: >-
      The ClinGen DCM gene curation places TNNC1 in the definitive-evidence tier,
      independently of the later gene-validity assertion.
  - reference: PMID:31983221
    reference_title: Reevaluating the Genetic Contribution of Monogenic Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Variants in MYH7, LMNA, BAG3, TNNT2, TNNC1, PLN, ACTC1, NEXN, TPM1, and VCL
      were significantly enriched in specific patient subsets
    explanation: >-
      Case-control rare-variant burden analysis across 2538 DCM patients confirms a
      statistically robust TNNC1 excess, independent of candidate-gene reporting
      bias.
  - reference: CGGV:assertion_5d832673-8acb-4a02-ae34-35e0d9981b70-2023-09-13T160000.000Z
    reference_title: TNNC1 / hypertrophic cardiomyopathy (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      TNNC1 | HGNC:11943 | hypertrophic cardiomyopathy | MONDO:0005045 | AD |
      Definitive
    explanation: >-
      Documents the allelic pleiotropy caveat: the same gene carries a Definitive
      relationship with hypertrophic cardiomyopathy, so a TNNC1 variant does not by
      itself predict the dilated phenotype. PARTIAL because it concerns a sibling
      phenotype rather than CMD1Z.
  - reference: PMID:36814108
    reference_title: "A novel variant of TNNC1 associated with severe dilated cardiomyopathy causing infant mortality and stillbirth: a case of germline mosaicism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The American College of Medical Genetics and Genomics recently added TNNC1
      to their recommended list of genes for reporting secondary findings.
    explanation: >-
      Supports the clinical-actionability status of TNNC1 that drives its inclusion
      on cardiomyopathy panels and in secondary-findings reporting.
diagnosis:
- name: Echocardiography
  description: >-
    First-line imaging. Left ventricular dimensions and ejection fraction establish
    the dilated phenotype, and diastolic indices (E/A ratio, tissue-Doppler E'/A',
    atrial size) capture the filling abnormality that can be the earliest finding in
    a TNNC1 carrier. Echocardiography is also the surveillance modality for
    genotype-positive, phenotype-negative relatives identified by cascade testing.
  diagnosis_term:
    preferred_term: echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  evidence:
  - reference: PMID:31073128
    reference_title: Dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Echocardiography and other imaging techniques are required to assess
      ventricular dysfunction and adverse myocardial remodelling, and
      immunological and histological analyses of an endomyocardial biopsy sample
      are indicated when inflammation or infection is suspected.
    explanation: >-
      Establishes echocardiography as the required modality for assessing
      ventricular dysfunction and remodeling in DCM. Evidence source is OTHER
      because this is a review.
  - reference: PMID:40671656
    reference_title: Cardiac Troponin C E135A Variant Impairs Myofilament Response to PKA Phosphorylation and Is Associated With Autosomal Dominant Dilated Cardiomyopathy With Diastolic Dysfunction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She was subsequently diagnosed with nonischemic DCM with class I diastolic
      dysfunction by echocardiogram and had an implantable cardioverter-defibrillator
      (ICD) placed.
    explanation: >-
      Worked example in a TNNC1 family: echocardiography simultaneously established
      the dilated phenotype and graded the diastolic abnormality.
- name: Cardiac Magnetic Resonance Imaging with Late Gadolinium Enhancement
  description: >-
    Cardiac MRI quantifies chamber volumes and function more reproducibly than
    echocardiography and, with late gadolinium enhancement, distinguishes
    replacement fibrosis from its absence. In the E135A family it specifically
    excluded scar in an adolescent carrier with a reduced ejection fraction, which
    is informative because absence of late enhancement argues against a burnt-out
    myocarditic or ischemic cause and supports a primary myofilament disease.
  diagnosis_term:
    preferred_term: cardiac magnetic resonance imaging with late gadolinium enhancement
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:40671656
    reference_title: Cardiac Troponin C E135A Variant Impairs Myofilament Response to PKA Phosphorylation and Is Associated With Autosomal Dominant Dilated Cardiomyopathy With Diastolic Dysfunction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Then, cardiac MRI was performed specifically to evaluate for fibrosis/scar.
      The dilation and reduced EF were confirmed and furthermore, there was no
      evidence of scar by gadolinium enhancement and no delayed enhancement of the
      myocardium.
    explanation: >-
      Documents the specific diagnostic role of cardiac MRI in a TNNC1 carrier:
      confirming the dilated phenotype while excluding scar.
- name: Cardiomyopathy Multigene Panel Sequencing
  description: >-
    The confirmatory test is molecular. TNNC1 is a definitive-evidence DCM gene and
    is included on clinically curated cardiomyopathy panels alongside TTN, LMNA,
    MYH7, TNNT2, BAG3, DES, FLNC, PLN, RBM20 and SCN5A; exome or genome sequencing
    is a reasonable second tier. Two interpretive caveats are specific to this gene:
    most reported TNNC1 variants are de novo, so familial segregation evidence is
    often unavailable, and TNNC1 variants also cause hypertrophic and restrictive
    disease, so a variant must be read against the observed phenotype rather than
    assumed to be a CMD1Z allele.
  diagnosis_term:
    preferred_term: cardiomyopathy multigene panel sequencing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:33947203
    reference_title: Evidence-Based Assessment of Genes in Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical genetic testing panels include most high-evidence genes; however,
      genes lacking robust evidence are also commonly included.
    explanation: >-
      The ClinGen DCM panel's finding about panel composition, which is the
      interpretive framework this diagnostic entry applies; TNNC1 falls in the
      high-evidence set.
  - reference: PMID:40671656
    reference_title: Cardiac Troponin C E135A Variant Impairs Myofilament Response to PKA Phosphorylation and Is Associated With Autosomal Dominant Dilated Cardiomyopathy With Diastolic Dysfunction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Given the family history of DCM, gene panel testing for cardiomyopathy and
      arrhythmia associated genes was performed for the proband (III.2) with
      cascade testing performed in II.2, II.3, IV.2, and IV.4.
    explanation: >-
      Worked example of the panel-then-cascade testing pathway in a TNNC1 family.
- name: Exclusion of Loading Conditions and Coronary Disease
  description: >-
    DCM is definitionally a diagnosis of exclusion: the dilation and systolic
    impairment must not be explained by hypertension, valvular disease, or coronary
    artery disease, and the acquired causes (myocarditis, alcohol and other toxins,
    the peripartum state, tachyarrhythmia, endocrine and autoimmune disease) must be
    considered before a genetic label is applied. A pathogenic TNNC1 genotype does
    not remove this step.
  evidence:
  - reference: PMID:31073128
    reference_title: Dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left
      ventricular or biventricular dilation and impaired contraction that is not
      explained by abnormal loading conditions (for example, hypertension and
      valvular heart disease) or coronary artery disease.
    explanation: >-
      States the exclusion criteria that define the DCM diagnosis. Evidence source
      is OTHER because this is a review.
  - reference: PMID:20301486
    reference_title: Dilated Cardiomyopathy Overview.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Provide the evaluation strategy of a proband with nonsyndromic DCM
    explanation: >-
      The GeneReviews DCM overview exists to supply this proband evaluation
      strategy, of which exclusion of non-genetic causes is the first step.
      Evidence source is OTHER because GeneReviews is an expert-authored review.
differential_diagnoses:
- name: Ischemic and other acquired dilated cardiomyopathy
  description: >-
    Coronary artery disease, hypertension, valvular disease, tachyarrhythmia,
    alcohol and other cardiotoxins, and endocrine or autoimmune disease all produce
    a dilated, hypocontractile ventricle and must be excluded before a genetic
    diagnosis is made.
  distinguishing_features:
  - Regional (coronary-territory) wall-motion abnormality or an ischemic late-gadolinium-enhancement pattern favors ischemic cardiomyopathy.
  - Absent family history plus an identified exposure or loading condition, with recovery after its removal, favors an acquired cause.
  evidence:
  - reference: PMID:31073128
    reference_title: Dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left
      ventricular or biventricular dilation and impaired contraction that is not
      explained by abnormal loading conditions (for example, hypertension and
      valvular heart disease) or coronary artery disease.
    explanation: >-
      The definition itself enumerates the acquired conditions that must be
      excluded. Evidence source is OTHER because this is a review.
- name: TTN-truncating and other high-evidence genetic dilated cardiomyopathy
  description: >-
    TTN truncating variants are the single most common identifiable genetic cause of
    DCM, and LMNA, BAG3, FLNC, RBM20, DES, PLN, SCN5A, MYH7 and TNNT2 account for
    most of the remainder. These are clinically indistinguishable from CMD1Z at the
    bedside; the discrimination is molecular.
  distinguishing_features:
  - LMNA and DES disease is typically preceded by conduction-system disease and atrioventricular block; TNNC1 disease is not characteristically conduction-first.
  - Only a multigene panel or broader sequencing separates the genotypes; imaging and clinical course overlap substantially.
  evidence:
  - reference: PMID:31983221
    reference_title: Reevaluating the Genetic Contribution of Monogenic Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Truncating variants in TTN and DSP were associated with DCM in all
      comparisons.
    explanation: >-
      Identifies the highest-yield alternative genotypes that a TNNC1 diagnosis must
      be distinguished from.
- name: TNNC1-related hypertrophic and restrictive cardiomyopathy
  description: >-
    The same gene produces hypertrophic (CMH13) and restrictive phenotypes through
    different substitutions, with ClinGen classifying the TNNC1-hypertrophic
    relationship as Definitive in parallel with the dilated one. A TNNC1 variant on
    a panel report therefore does not establish CMD1Z; the phenotype does.
  distinguishing_features:
  - Increased wall thickness without dilation, and myofilament variants that increase rather than decrease thin-filament Ca2+ affinity, indicate the hypertrophic expression.
  - A small, stiff, non-dilated ventricle with severe diastolic impairment and biatrial enlargement indicates the restrictive expression.
  evidence:
  - reference: CGGV:assertion_5d832673-8acb-4a02-ae34-35e0d9981b70-2023-09-13T160000.000Z
    reference_title: TNNC1 / hypertrophic cardiomyopathy (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      TNNC1 | HGNC:11943 | hypertrophic cardiomyopathy | MONDO:0005045 | AD |
      Definitive
    explanation: >-
      ClinGen records a parallel Definitive TNNC1-hypertrophic cardiomyopathy
      relationship, which is precisely why the phenotypic distinction must be made
      clinically rather than genetically.
  - reference: PMID:17932326
    reference_title: Dilated and hypertrophic cardiomyopathy mutations in troponin and alpha-tropomyosin have opposing effects on the calcium affinity of cardiac thin filaments.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Both HCM mutations increased Ca(2+) affinity (DeltapCa(50)=+0.41+/-0.02 and
      +0.51+/-0.01), whereas the dilated cardiomyopathy mutations decreased affinity
    explanation: >-
      Gives the functional discriminator between the dilated and hypertrophic
      expressions of thin-filament variants.
progression:
- phase: Genotype-positive, phenotype-negative
  notes: >-
    A relative identified by cascade testing may carry the TNNC1 variant with normal
    imaging. Penetrance in the founding G159D kindred was 100%, but that is a
    single-pedigree figure; population data on DCM-gene carriers put combined
    clinical plus subclinical penetrance at no more than about 30%. Surveillance
    rather than treatment is the correct posture at this stage, with attention to
    diastolic indices since these can be the first abnormality in TNNC1 families.
  evidence:
  - reference: PMID:15542288
    reference_title: Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prevalence of TNNC1/TNNT2 mutations in familial DCM was 5% with a
      penetrance of 100%.
    explanation: >-
      The complete-penetrance figure for the founding cohort. PARTIAL because it
      derives from ascertained mutation-positive families and cannot be generalized
      to unselected carriers.
  - reference: PMID:35708014
    reference_title: Frequency, Penetrance, and Variable Expressivity of Dilated Cardiomyopathy-Associated Putative Pathogenic Gene Variants in UK Biobank Participants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The combined clinical/subclinical penetrance was ≤30% with all 3 variant
      filtering strategies.
    explanation: >-
      Quantifies incomplete penetrance across DCM genes in an unselected population
      cohort, the counterweight to the founding pedigree's 100% figure. PARTIAL
      because the estimate is across DCM genes rather than TNNC1-specific.
- phase: Manifest dilated cardiomyopathy
  notes: >-
    Once the phenotype declares itself the course is progressive rather than
    episodic, with dilation, falling ejection fraction, and symptomatic heart
    failure. Onset spans infancy to the fifth decade, so the phase is not tied to a
    life stage.
  evidence:
  - reference: PMID:15542288
    reference_title: Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The disease expression associated with TNNC1 and TNNT2 mutations was severe
      with complete penetrance.
    explanation: >-
      Characterizes the manifest phase as severe in troponin-gene DCM.
- phase: End-stage heart failure, transplantation or sudden death
  notes: >-
    The terminal phase. In the founding cohort a majority of the 21 troponin
    mutation carriers reached transplantation or death; sudden arrhythmic death
    occurred at a mean age of 29 years, and can precede end-stage pump failure.
  evidence:
  - reference: PMID:15542288
    reference_title: Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The data suggest that mutation analysis of the troponin complex in DCM
      patients may prove valuable in early identification of individuals with an
      adverse prognosis and a high risk of premature death.
    explanation: >-
      States the adverse-prognosis conclusion that defines this phase and motivates
      early genotyping.
treatments:
- name: Guideline-Directed Heart Failure Pharmacotherapy
  description: >-
    Standard heart-failure therapy for left ventricular systolic dysfunction — the
    four contemporary HFrEF pillars: an angiotensin receptor-neprilysin inhibitor
    (or an ACE inhibitor / angiotensin receptor blocker where ARNI is not
    tolerated), a beta-blocker, a mineralocorticoid receptor antagonist, and an
    SGLT2 inhibitor — targeting the neurohormonal amplifier of adverse remodeling.
    There is no TNNC1-specific disease-modifying therapy, so management is the
    generic DCM regimen. Note the mechanistic tension worth recording for this
    genotype: several TNNC1 variants abolish the myofilament response to
    PKA-mediated (beta-adrenergic) phosphorylation, so the myofilament substrate
    that beta-blockade normally protects is already unresponsive; whether this
    alters the benefit of beta-blockade in TNNC1 carriers has not been studied.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: angiotensin receptor-neprilysin inhibitor (sacubitril/valsartan)
      term:
        id: NCIT:C190796
        label: Angiotensin Receptor-Neprilysin Inhibitor
    - preferred_term: ACE inhibitor (alternative to ARNI)
      term:
        id: NCIT:C247
        label: ACE Inhibitor
    - preferred_term: beta-blocker
      term:
        id: NCIT:C29576
        label: Beta-Adrenergic Antagonist
    - preferred_term: mineralocorticoid receptor antagonist (spironolactone as the class exemplar)
      term:
        id: NCIT:C840
        label: Spironolactone
    - preferred_term: SGLT2 inhibitor
      term:
        id: NCIT:C98083
        label: SGLT2 Inhibitor
  target_mechanisms:
  - target: Neurohormonal Activation
    treatment_effect: INHIBITS
    description: >-
      Neurohormonal blockade interrupts the maladaptive amplifier between the
      primary thin-filament lesion and adverse ventricular remodeling.
  evidence:
  - reference: PMID:31073128
    reference_title: Dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      As DCM eventually leads to impaired contractility, standard approaches to
      prevent or treat heart failure are the first-line treatment for patients with
      DCM.
    explanation: >-
      Establishes standard heart-failure therapy as first-line management for
      dilated cardiomyopathy, of which CMD1Z is a genetic form. Evidence source is
      OTHER because this is a review.
  - reference: PMID:36158814
    reference_title: "Thin filament cardiomyopathies: A review of genetics, disease mechanisms, and emerging therapeutics."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      None of these therapies directly address the underlying sarcomeric
      dysfunction associated with thin-filament mutations.
    explanation: >-
      Records the therapeutic gap: the available regimen treats the downstream
      neurohormonal amplifier, not the myofilament lesion. PARTIAL because it is a
      statement of what the therapy does not do.
- name: Implantable Cardioverter Defibrillator
  description: >-
    Device therapy for primary or secondary prevention of sudden cardiac death.
    Particularly relevant in CMD1Z because sudden arrhythmic death occurred at a
    mean age of 29 years in the founding cohort and because ventricular fibrillation
    has been the presenting event in a TNNC1 carrier with only moderately reduced
    ejection fraction.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
  notes: >-
    Indication follows general cardiomyopathy and arrhythmia guidelines; no
    TNNC1-specific arrhythmic risk-stratification rule has been validated.
  evidence:
  - reference: PMID:40671656
    reference_title: Cardiac Troponin C E135A Variant Impairs Myofilament Response to PKA Phosphorylation and Is Associated With Autosomal Dominant Dilated Cardiomyopathy With Diastolic Dysfunction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She was subsequently diagnosed with nonischemic DCM with class I diastolic
      dysfunction by echocardiogram and had an implantable cardioverter-defibrillator
      (ICD) placed.
    explanation: >-
      Documents ICD implantation in a TNNC1 variant carrier after a resuscitated
      ventricular fibrillation arrest.
  - reference: PMID:31073128
    reference_title: Dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Cardiac resynchronization therapy and implantable cardioverter-defibrillators
      may be required to prevent life-threatening arrhythmias.
    explanation: >-
      Establishes device therapy for arrhythmic protection as part of standard DCM
      management. Evidence source is OTHER because this is a review.
- name: Cardiac Resynchronization Therapy
  description: >-
    Biventricular pacing for carriers with persistent systolic dysfunction and a
    significant intraventricular conduction delay, correcting the mechanical
    dyssynchrony that compounds an already underperforming ventricle. Indication
    follows general heart-failure criteria; no TNNC1-specific selection rule
    exists, and the thin-filament lesion itself is untouched by resynchronization.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: cardiac resynchronization therapy
    term:
      id: NCIT:C80436
      label: Cardiac Resynchronization Therapy
  evidence:
  - reference: PMID:31073128
    reference_title: Dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Cardiac resynchronization therapy and implantable cardioverter-defibrillators
      may be required to prevent life-threatening arrhythmias.
    explanation: >-
      Names cardiac resynchronization therapy alongside defibrillator therapy as
      part of standard dilated cardiomyopathy device management. Evidence source is
      OTHER because this is a review.
- name: Mechanical Circulatory Support
  description: >-
    Durable left ventricular assist device support for carriers refractory to
    medical therapy, used as a bridge to transplantation or as destination therapy.
    It is the escalation step between guideline-directed pharmacotherapy and
    transplantation, and is particularly relevant in this disorder because the
    founding cohort reached transplantation or death in the majority of carriers.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: left ventricular assist device insertion
    term:
      id: NCIT:C172327
      label: Left Ventricular Assist Device Insertion
  evidence:
  - reference: PMID:28190577
    reference_title: Dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Patients who are refractory to medical therapy might benefit from mechanical
      circulatory support and heart transplantation.
    explanation: >-
      Establishes mechanical circulatory support as the escalation option for
      medically refractory dilated cardiomyopathy, of which CMD1Z is a genetic
      form. Evidence source is OTHER because this is a seminar review.
- name: Cascade Genetic Testing and Counseling
  description: >-
    Predictive TNNC1 testing and cardiac surveillance of first-degree relatives.
    Counseling must address two features peculiar to this gene: onset spans infancy
    to the fifth decade so a normal echocardiogram in adulthood does not clear a
    carrier's children, and many TNNC1 variants arise de novo — with at least one
    documented instance of germline mosaicism causing recurrent perinatal loss — so
    an apparently negative parental test does not guarantee a low recurrence risk.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301486
    reference_title: Dilated Cardiomyopathy Overview.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Provide a basic view of genetic risk assessment of at-risk asymptomatic
      relatives of a proband with DCM to inform cardiac surveillance and allow early
      detection and treatment of DCM to improve long-term outcome.
    explanation: >-
      The GeneReviews DCM overview frames genetic risk assessment of at-risk
      asymptomatic relatives, with cardiac surveillance for early detection, as
      precisely this intervention. Evidence source is OTHER because GeneReviews is
      an expert-authored review resource.
  - reference: PMID:36814108
    reference_title: "A novel variant of TNNC1 associated with severe dilated cardiomyopathy causing infant mortality and stillbirth: a case of germline mosaicism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The identification of the same de novo variant in all affected siblings is
      suggestive of germline mosaicism in this family.
    explanation: >-
      The specific counseling hazard: germline mosaicism produces recurrence risk
      that parental testing does not capture.
  - reference: PMID:15542288
    reference_title: Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The data suggest that mutation analysis of the troponin complex in DCM
      patients may prove valuable in early identification of individuals with an
      adverse prognosis and a high risk of premature death.
    explanation: >-
      The founding argument for cascade genotyping in troponin-gene DCM.
- name: Heart Transplantation
  description: >-
    Advanced therapy for end-stage heart failure, with mechanical circulatory
    support as a bridge. Transplantation is not a rare tail event in this disorder:
    6 of 21 carriers in the founding troponin cohort were transplanted, and the
    explanted CMD1Z myocardium obtained at transplantation has been the source of
    the only human-tissue mechanical studies of this disease.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Organ transplantation
    term:
      id: NCIT:C15289
      label: Organ Transplantation
  evidence:
  - reference: PMID:15542288
    reference_title: Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A total of 21 mutation carriers were identified; 6 underwent cardiac
      transplantation, 5 died of heart failure, and 4 died suddenly at a mean age
      of 29 years, while 6 remained stable on medication.
    explanation: >-
      Quantifies transplantation as an outcome in the founding troponin mutation
      cohort, with the denominator explicit: 6 of 21 carriers were transplanted.
  - reference: PMID:19808376
    reference_title: Functional analysis of a unique troponin c mutation, GLY159ASP, that causes familial dilated cardiomyopathy, studied in explanted heart muscle.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We studied the Ca(2+)-regulatory properties of myocytes and troponin
      extracted from the explanted heart of a patient with inherited dilated
      cardiomyopathy due to the cTnC G159D mutation.
    explanation: >-
      Documents that a G159D carrier progressed to transplantation. PARTIAL because
      this is incidental evidence of transplant use rather than an efficacy study.
experimental_models:
- name: cTnC D73N knock-in mouse
  description: >-
    Heterozygous knock-in mice carrying an engineered D73N substitution in the
    regulatory N-domain of cardiac troponin C, designed to reduce thin-filament Ca2+
    sensitivity by accelerating Ca2+ dissociation. The mice show decreased Ca2+
    sensitivity of force development in skinned trabeculae, increased left
    ventricular dimensions with thinner walls, dramatically reduced ejection
    fraction and fractional shortening, prolonged QRS and QT intervals, and
    ventricular myocytes that fail to respond to beta-adrenergic stimulation, with a
    median survival of 12 weeks. It is the only in vivo model of a cTnC-driven
    dilated phenotype, and it establishes sufficiency of N-domain Ca2+
    desensitization — but the allele is explicitly not a human disease variant (see
    the HUMAN_MODEL_MISMATCH discussion).
  experimental_model_type: OTHER
  organism:
    preferred_term: house mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:26379556
    reference_title: Knock-in mice harboring a Ca(2+) desensitizing mutation in cardiac troponin C develop early onset dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
        Kaplan-Meier survival analysis revealed that median survival time for
        knock-in mice was 12 weeks.
    explanation: >-
        Documents the model's defining survival phenotype, the headline readout of
        this experimental system.
  publication: PMID:26379556
- name: cTnC-depleted human donor cardiac muscle preparations reconstituted with recombinant mutant cTnC
  description: >-
    Permeabilized myocardial strips from a non-failing human donor heart are
    depleted of endogenous cTnC with CDTA and reconstituted with a 50:50 mixture of
    recombinant wild-type and mutant cTnC to mimic the heterozygous state, then
    assayed for steady-state isometric force versus pCa, cooperativity, sinusoidal
    stiffness, rate of tension redevelopment, and the response to PKA incubation.
    This is the closest available human-tissue system for testing a candidate TNNC1
    variant and was the system in which E135A was shown to abolish the PKA response.
    The porcine papillary equivalent was used for the earlier Y5H/M103I/D145E/I148V
    and D132N characterizations.
  experimental_model_type: OTHER
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  cell_source: Permeabilized left ventricular strips from a non-failing human donor heart
  evidence:
  - reference: PMID:40671656
    reference_title: Cardiac Troponin C E135A Variant Impairs Myofilament Response to PKA Phosphorylation and Is Associated With Autosomal Dominant Dilated Cardiomyopathy With Diastolic Dysfunction.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
        cTnC-depleted donor human cardiac muscle preparations were reconstituted
        with recombinant exogenous human cTnC-E135A. Steady-state isometric force
        and crossbridge kinetics were measured before and after PKA incubation.
    explanation: >-
        Describes the preparation and the measurements this model system supports.
  publication: PMID:40671656
- name: Explanted CMD1Z (G159D) human myocardium
  description: >-
    Myocytes and troponin extracted from the explanted heart of a G159D carrier at
    transplantation, studied by skinned-myocyte force-pCa measurement, in vitro
    motility assay of reconstituted thin filaments, and mass spectrometry of
    troponin phosphorylation state. The only study of native CMD1Z myocardium, and
    the source of the phosphorylation-uncoupling model — notably, it contradicted
    the direction of the Ca2+-sensitivity change predicted by prior reconstituted
    systems.
  experimental_model_type: OTHER
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  cell_source: Explanted left ventricular myocardium from a patient with the TNNC1 G159D variant
  evidence:
  - reference: PMID:19808376
    reference_title: Functional analysis of a unique troponin c mutation, GLY159ASP, that causes familial dilated cardiomyopathy, studied in explanted heart muscle.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
        In vitro, these mutations decrease Ca(2+) sensitivity and cross-bridge
        turnover rate, but the mutations have not been investigated in human
        tissue.
    explanation: >-
        States what makes this model system unique: it is the first study of these
        thin-filament mutations in native human tissue rather than reconstituted
        systems.
  publication: PMID:19808376
- name: Xenopus tropicalis TNNC1 CRISPR/Cas9 knockout
  description: >-
    CRISPR/Cas9 knockout of tnnc1 in Xenopus tropicalis produced a tadpole cardiac
    phenotype consistent with dilated cardiomyopathy. Its documented limitation is
    instructive: the authors could not rescue the tadpole hearts with either
    wild-type or patient-variant human cTnC, so the model could not be used to test
    variant-specific effects and the study fell back on reconstituted mammalian
    muscle preparations.
  experimental_model_type: OTHER
  organism:
    preferred_term: western clawed frog
    term:
      id: NCBITaxon:8364
      label: Xenopus tropicalis
  evidence:
  - reference: PMID:32038292
    reference_title: Familial Dilated Cardiomyopathy Associated With a Novel Combination of Compound Heterozygous TNNC1 Variants.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
        We began our investigation with CRISPR/Cas9 knockout of TNNC1 in Xenopus
        tropicalis, which resulted in a cardiac phenotype in tadpoles consistent
        with DCM.
    explanation: >-
        Establishes the knockout model and its DCM-consistent tadpole phenotype.
  publication: PMID:32038292
discussions:
- discussion_id: tnnc1_mechanism_direction_conflict
  prompt: >-
    Does the founding CMD1Z variant G159D cause dilated cardiomyopathy by
    desensitizing the myofilament to calcium, as the canonical thin-filament model
    predicts, or by uncoupling troponin phosphorylation from calcium sensitivity —
    and why do reconstituted systems and native patient myocardium give opposite
    answers?
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - pathophysiology#Altered Myofilament Calcium Sensitivity
  - pathophysiology#Uncoupling of Troponin Phosphorylation from Calcium Sensitivity
  rationale: >-
    The canonical model, built from reconstituted thin filaments, holds that DCM
    variants lower and hypertrophic variants raise myofilament Ca2+ sensitivity. For
    G159D this prediction fails in the one system closest to the disease: in
    myocytes from an explanted G159D heart the Ca2+ sensitivity was higher than
    donor myocardium, while in reconstituted fibres it was unchanged and the defect
    was purely kinetic. The authors of the explanted-tissue study attribute the
    discrepancy to native post-translational modification state — reconstituted
    systems lack the endogenous troponin I and troponin T phosphorylation that
    modulates how a mutation behaves. This matters beyond G159D: it implies that
    variant-classification pipelines built on reconstituted-system Ca2+ sensitivity
    may systematically mispredict the direction of effect, and therefore the
    phenotype, for TNNC1 alleles.
  evidence:
  - reference: PMID:19808376
    reference_title: Functional analysis of a unique troponin c mutation, GLY159ASP, that causes familial dilated cardiomyopathy, studied in explanted heart muscle.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The differences between these data and previous in vitro results show that
      native phosphorylation of troponin I and troponin T and other
      posttranslational modifications of sarcomeric proteins strongly influence the
      functional effects of a mutation.
    explanation: >-
      The authors explicitly identify the system-dependence of the measured effect
      as the source of the conflict, which is the substance of this controversy.
  - reference: PMID:17021793
    reference_title: Functional effects of the DCM mutant Gly159Asp troponin C in skinned muscle fibres.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Gly159Asp TnC had no significant effect on either the Ca(2+) sensitivity or
      cooperativity of force generation when compared to wild type.
    explanation: >-
      The reconstituted-fibre result that disagrees with both the canonical
      prediction and the explanted-tissue measurement, establishing the three-way
      discrepancy.
  proposed_experiments:
  - experiment_id: tnnc1_cross_variant_human_force_pca_panel
    name: Cross-variant force-pCa and PKA panel in one human preparation
    description: >-
      Measure the force-pCa relationship and the PKA response for a panel of TNNC1
      variants side by side in the same cTnC-depleted human donor myocardium system,
      so that direction-of-effect comparisons are not confounded by species or
      preparation.
    decision_criterion: >-
      If desensitizing and sensitizing TNNC1 variants both reproduce their published
      directions in one common human preparation, the discrepancy is genotype-driven;
      if the directions converge, it was preparation-driven.
  - experiment_id: tnnc1_paired_phosphostoichiometry_calcium_sensitivity
    name: Paired phosphorylation-stoichiometry and calcium-sensitivity assay
    description: >-
      Assay troponin I Ser23/24 phosphorylation stoichiometry alongside each
      Ca2+-sensitivity measurement, to test directly whether native phosphorylation
      state accounts for the reconstituted-versus-explanted discrepancy.
    decision_criterion: >-
      If Ca2+-sensitivity direction tracks measured phosphorylation stoichiometry
      rather than the variant identity, the uncoupling model subsumes the
      desensitization result.
- discussion_id: tnnc1_d73n_mouse_model_mismatch
  prompt: >-
    Does the D73N knock-in mouse, whose substitution is explicitly not known to cause
    human disease, faithfully model the pathophysiology of human TNNC1 dilated
    cardiomyopathy?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Altered Myofilament Calcium Sensitivity
  - pathophysiology#Adverse Ventricular Remodeling
  rationale: >-
    The only in vivo model of cTnC-driven dilated cardiomyopathy carries D73N, a
    substitution the authors engineered to reduce Ca2+ sensitivity and which they
    state is not known to be associated with heart disease in human patients. It
    demonstrates sufficiency — desensitizing the cTnC regulatory domain alone
    produces DCM in a mouse — but it cannot demonstrate necessity or fidelity for the
    human alleles. The mismatch is not merely formal: the best-studied human allele,
    G159D, sits in the structural C-domain rather than the regulatory N-domain, and
    in patient myocardium it raised rather than lowered Ca2+ sensitivity, so the
    mouse models the mechanism the human variant does not exhibit. No G159D or E135A
    knock-in mouse has been reported. Claims about CMD1Z pathophysiology sourced from
    this model are marked MODEL_ORGANISM in this entry and should be read as support
    for the desensitization hypothesis group, not as genotype-matched evidence.
  evidence:
  - reference: PMID:26379556
    reference_title: Knock-in mice harboring a Ca(2+) desensitizing mutation in cardiac troponin C develop early onset dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we generated knock-in mice carrying a D73N mutation (not known to be
      associated with heart disease in human patients) in cTnC
    explanation: >-
      The model's own authors state that the modeled allele is not a human disease
      variant, which is the mismatch this discussion records.
  - reference: PMID:19808376
    reference_title: Functional analysis of a unique troponin c mutation, GLY159ASP, that causes familial dilated cardiomyopathy, studied in explanted heart muscle.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Maximal Ca(2+)-activated force was similar in cTnC G159D and donor myocytes,
      but the Ca(2+) sensitivity of cTnC G159D myocytes was higher (EC(50)
      G159D/donor=0.60).
    explanation: >-
      Shows the direction of the human G159D effect is opposite to the desensitizing
      lesion engineered into the mouse, sharpening the mismatch from a formal to a
      mechanistic one.
  proposed_experiments:
  - experiment_id: tnnc1_genotype_matched_knockin_mouse
    name: Genotype-matched TNNC1 knock-in mouse
    description: >-
      Generate a G159D or E135A knock-in mouse and test whether it reproduces the
      dilated phenotype and, specifically, the loss of beta-adrenergic myofilament
      responsiveness observed in human tissue.
    decision_criterion: >-
      Reproduction of the dilated phenotype together with a blunted myofilament PKA
      response would validate the mouse route for the human alleles; a normal or
      hypertrophic phenotype would confine the D73N result to the engineered allele.
  - experiment_id: tnnc1_patient_ipsc_cardiomyocytes_isogenic
    name: Patient-derived TNNC1 iPSC-cardiomyocytes with isogenic controls
    description: >-
      Derive induced pluripotent stem cell cardiomyocytes from TNNC1 variant
      carriers, with isogenic CRISPR-corrected controls, to obtain a human in vitro
      system that retains native post-translational modification and can be assayed
      for contractility, calcium handling, and beta-adrenergic response.
    decision_criterion: >-
      Concordance between iPSC-cardiomyocyte and explanted-myocardium measurements
      would establish the iPSC system as the human-relevant assay in place of the
      mouse.
- discussion_id: tnnc1_calcium_sensitizer_therapeutic_direction
  prompt: >-
    Should therapy for TNNC1 dilated cardiomyopathy aim to restore myofilament
    calcium sensitivity, and if so, how should the direction of correction be chosen
    for a given variant?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Altered Myofilament Calcium Sensitivity
  - pathophysiology#Uncoupling of Troponin Phosphorylation from Calcium Sensitivity
  rationale: >-
    Troponin C is an unusually attractive drug target because it is the Ca2+ sensor
    itself, and engineered TnC constructs have been shown to correct abnormal
    thin-filament Ca2+ sensitivity in both directions, restoring actomyosin ATPase
    activity and force generation in skinned trabeculae. But no such agent exists for
    patients, and the direction of correction is genotype-dependent in a way that is
    not currently predictable: TNNC1 variants desensitize (Y5H, M103I, D132N, E135A),
    sensitize (D145E, and G159D in native myocardium), or leave steady-state
    sensitivity unchanged while slowing activation (G159D in reconstituted fibres). A
    variant-agnostic calcium sensitizer could therefore help one CMD1Z patient and
    harm another. The gap is twofold: no myofilament-directed therapy has reached
    TNNC1 patients, and no validated assay exists for assigning an individual variant
    to a correction direction.
  evidence:
  - reference: PMID:22511780
    reference_title: Engineered troponin C constructs correct disease-related cardiac myofilament calcium sensitivity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Rationally engineered TnC constructs corrected the abnormal Ca(2+)
      sensitivities of the thin filament, reconstituted actomyosin ATPase activity,
      and force generation in skinned trabeculae.
    explanation: >-
      Establishes proof of principle that resetting thin-filament Ca2+ sensitivity is
      achievable, which is what makes the unanswered direction-of-correction question
      actionable rather than academic.
  - reference: PMID:36158814
    reference_title: "Thin filament cardiomyopathies: A review of genetics, disease mechanisms, and emerging therapeutics."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      With mounting evidence that thin filament cardiomyopathies occur through a
      distinct mechanism, there is need for therapies targeting the unique,
      underlying mechanisms tailored for each patient depending on a given mutation.
    explanation: >-
      States the per-variant tailoring requirement that constitutes the knowledge
      gap. Evidence source is OTHER because this is a review.
  proposed_experiments:
  - experiment_id: tnnc1_standardized_human_variant_triage_assay
    name: Standardized human variant-triage assay for TNNC1
    description: >-
      Build a standardized human cTnC-depleted myocardium assay that reports both
      steady-state Ca2+ sensitivity and PKA responsiveness for any candidate TNNC1
      variant, and validate it against variants with known clinical phenotypes.
    decision_criterion: >-
      The assay is usable for triage if its two readouts separate variants with known
      dilated from known hypertrophic clinical phenotypes.
  - experiment_id: tnnc1_direction_specific_pharmacology_panel
    name: Direction-specific pharmacology across a TNNC1 variant panel
    description: >-
      Test whether calcium sensitizers and myofilament-directed agents produce
      genotype-dependent, direction-specific effects across a panel of desensitizing
      and sensitizing TNNC1 variants in the same preparation.
    decision_criterion: >-
      If a sensitizer corrects desensitizing variants but worsens sensitizing ones,
      myofilament therapy in TNNC1 disease must be genotype-gated rather than applied
      to CMD1Z as a class.
references:
- reference: PMID:20301486
  title: Dilated Cardiomyopathy Overview.
  tags:
  - GeneReviews
- reference: PMID:26232335
  title: "Structure and function of cardiac troponin C (TNNC1): Implications for heart failure, cardiomyopathies, and troponin modulating drugs."
- reference: PMID:36158814
  title: "Thin filament cardiomyopathies: A review of genetics, disease mechanisms, and emerging therapeutics."
notes: >-
  Scope: this entry models MONDO:0012745 (dilated cardiomyopathy 1Z), the
  TNNC1-related dilated node of the TNNC1 allelic series, and conforms to the
  cardiomyopathy_maladaptive_remodeling module at five nodes. The hypertrophic
  (CMH13) and restrictive expressions of TNNC1 variation appear here only as
  spectrum context and in the differential diagnosis; ClinGen curates the
  TNNC1-hypertrophic relationship as a separate Definitive assertion.

  Named Entity Confusion preflight (per CLAUDE.md): MONDO:0012745 was verified with
  OAK before curation — the definition names TNNC1 as the causal gene ("Any familial
  isolated dilated cardiomyopathy in which the cause of the disease is a mutation in
  the TNNC1 gene"), the OMIM xref is OMIM:611879, the HGNC relationship is
  RO:0004003 HGNC:11943, and synonyms include CMD1Z and "TNNC1 familial isolated
  dilated cardiomyopathy". Every curated citation concerns TNNC1. Two identifier
  corrections were made against the deep-research report, which asserted HGNC:11940
  for TNNC1 (that identifier is TNK1; the correct one is hgnc:11943, verified with
  OAK) and suggested HP:0025168 for reduced ejection fraction (HP:0025168 is Left
  ventricular diastolic dysfunction; reduced ejection fraction is HP:0012664).

  Mechanism modeling: the three pathophysiology branches downstream of the trigger
  are curated as three explicit mechanistic_hypotheses groups rather than a single
  chain, because the literature genuinely disagrees. The canonical
  Ca2+-desensitization model is supported for Y5H, M103I, D132N and E135A and by the
  D73N mouse; the phosphorylation-uncoupling model comes from explanted G159D
  myocardium and is replicated for E135A and M103I; the kinetics model rests on the
  halved activation rate of G159D in skinned fibres. The
  tnnc1_mechanism_direction_conflict discussion records that these are not merely
  complementary — for G159D the reconstituted and native-tissue measurements point in
  opposite directions on Ca2+ sensitivity. The REFUTE-tagged evidence item on the
  Altered Myofilament Calcium Sensitivity node is deliberate: it preserves the
  counter-observation on the node it contradicts rather than hiding it.

  GeneReviews scope: there is no TNNC1-specific GeneReviews chapter (a PubMed search
  for TNNC1 GeneReviews returns only the disease-level "Dilated Cardiomyopathy
  Overview", PMID:20301486, and the "Nonsyndromic Hypertrophic Cardiomyopathy
  Overview"), so the applicable resource is the disease-level DCM overview, tagged
  accordingly in `references`. The indexed record carries a four-clause purpose
  statement rather than the full chapter text, so section-by-section GeneReviews
  mining is not possible from the cache; the two verbatim-quotable clauses are cited
  — the proband-evaluation clause on the diagnosis-by-exclusion entry and the
  at-risk-relative risk-assessment clause on cascade testing.

  Deep research: the claude_code provider was used
  (research/Dilated_Cardiomyopathy_1Z-deep-research-claude_code.md; 16 web searches,
  17 citations). The falcon (Edison) provider was attempted first per the default and
  returned HTTP 402 Payment Required; openscientist returned HTTP 401 Unauthorized.
  Every PMID, snippet and ontology term taken from the report was independently
  re-fetched and verified per the DR-verification SOP, and the two identifier errors
  noted above were caught by that process.

  Ventricular scope: the deep-research report asserted biventricular involvement,
  but it drew that from OMIM clinical-synopsis content it was unable to fetch (it
  recorded a 403), and no cited primary source supports it. The one report in which
  the right ventricle was explicitly followed found it normal throughout despite
  severe progressive left-sided disease (PMID:32038292), so the organ-level node is
  scoped to left ventricular involvement and that contrary observation is cited on
  it rather than a biventricular phenotype being asserted. Cardiomegaly is likewise
  not curated as a phenotype: the only support available is the increased
  heart-weight-to-body-weight ratio in the D73N mouse, and model-organism evidence
  should not be the sole support for a human phenotype — that mouse finding is
  already cited on the Adverse Ventricular Remodeling node, where it belongs.

  Diagnostics and treatments are modeled DCM-wide where no TNNC1-specific study
  exists, and those items are marked PARTIAL with the reason stated. Two points are
  genuinely TNNC1-specific: diastolic indices deserve attention on surveillance
  echocardiography because isolated diastolic dysfunction has been the presenting
  abnormality in a carrier, and counseling must address germline mosaicism because an
  apparently de novo TNNC1 variant has recurred in three siblings.

📚

References & Deep Research

References

3

PMID:20301486

Dilated Cardiomyopathy Overview.

No top-level findings curated for this source.

PMID:26232335

Structure and function of cardiac troponin C (TNNC1): Implications for heart failure, cardiomyopathies, and troponin modulating drugs.

No top-level findings curated for this source.

PMID:36158814

Thin filament cardiomyopathies: A review of genetics, disease mechanisms, and emerging therapeutics.

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Dilated Cardiomyopathy 1Z (CMD1Z) — Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 17 citations 2026-08-02T16:48:01.616914

Dilated Cardiomyopathy 1Z (CMD1Z) — Comprehensive Research Report

1. Disease Information

Overview: Dilated Cardiomyopathy 1Z (CMD1Z) is a rare, autosomal dominant form of familial isolated (non-syndromic) dilated cardiomyopathy caused by heterozygous mutation in TNNC1, the gene encoding cardiac (slow skeletal/cardiac-type) troponin C — the calcium-sensing subunit of the sarcomeric troponin complex. Affected individuals develop severe biventricular systolic dysfunction with markedly reduced left ventricular ejection fraction, often with early and aggressive disease progression requiring cardiac transplantation.

Key identifiers: - OMIM (phenotype): #611879 — CARDIOMYOPATHY, DILATED, 1Z; CMD1Z (OMIM.org) - OMIM (gene): 191040 — TROPONIN C, SLOW; TNNC1 (OMIM.org) - Gene locus: 3p21.1 - HGNC: TNNC1 (HGNC:11940) - GTR/UMLS: C2678475 (NCBI GTR) - ICD-10: I42.0 (Dilated cardiomyopathy — non-gene-specific parent code; no TNNC1-specific ICD-10/11 code exists) - MONDO: No TNNC1-subtype-specific MONDO term was identified in this search; CMD1Z falls under the broader "familial isolated dilated cardiomyopathy" umbrella (Orphanet ORPHA:154). This should be verified directly against the MONDO ontology before curation rather than assumed. - Orphanet:* TNNC1 is listed as a causal gene for familial isolated DCM (ORPHA:154) (Orphanet gene page)

Synonyms/alternative names: CMD1Z; Cardiomyopathy, dilated, 1Z; TNNC1-related dilated cardiomyopathy; Troponin C-related dilated cardiomyopathy.

Evidence basis: All primary reports of CMD1Z derive from individual patients and multi-generation pedigrees studied via genetic screening of DCM cohorts (not aggregated registry/database-level statistics) — principally a single large kindred (Family A) originally reported by Mogensen et al. (2004), later supplemented by additional sporadic/small-family TNNC1 variant reports (Chung/Hershberger group, 2011) and functional/biophysical follow-up studies on explanted patient myocardium.

2. Etiology

Disease causal factor: CMD1Z is a monogenic, sarcomeric-protein disease — it is caused directly by heterozygous missense mutation of TNNC1, not by environmental, infectious, or purely mechanistic/acquired factors. It belongs to the broader category of sarcomere-gene dilated cardiomyopathies (alongside TNNT2, TPM1, MYH7, ACTC1, TTN, etc.).

Genetic risk factors (causal variants): - The founding, best-characterized mutation is c.476G>A (p.Gly159Asp / G159D) in TNNC1, identified by Mogensen et al. in a large family (Family A) with severe DCM and complete penetrance (PMID: 15542288, J Am Coll Cardiol 2004). ClinVar classifies this variant as Pathogenic for CMD1Z (ClinVar RCV000013254, based on OMIM assertion; 0-star/no independent criteria review status — flagging a curatorial caveat that this classification has not undergone contemporary ACMG/AMP multi-lab review). - The mutation was absent in unaffected family members and in 200 ethnically matched control chromosomes, consistent with segregation and rarity. - Located at a conserved residue within a TnC domain that is constitutively occupied by Ca²⁺ (the structural C-domain, distinct from the regulatory N-domain). - Four additional rare TNNC1 variants — Y5H, M103I, D145E, I148V — were functionally characterized by Chung, Hershberger and colleagues (PMID: 21832052, J Biol Chem 2011), all previously reported in association with DCM cohorts, expanding the allelic series beyond the single founder G159D mutation. - TNNC1 also harbors a distinct set of variants (e.g., A8V, C84Y, E134D, D145E) associated instead with hypertrophic cardiomyopathy (CMH13) — TNNC1 is a genetically pleiotropic locus where different missense substitutions produce opposing (dilated vs. hypertrophic) myofilament calcium-sensitivity phenotypes. - Modifier/susceptibility genetic factors: Not specifically reported for CMD1Z; broader DCM literature implicates common variants and co-occurring "second hits" in genes such as TTN as modifiers of penetrance/severity in sarcomeric DCM generally, but no TNNC1-specific modifier locus has been published.

Environmental/lifestyle risk factors: None specifically documented for CMD1Z. As with other monogenic sarcomeric DCMs, generic DCM-exacerbating factors (alcohol, pregnancy/peripartum stress, tachyarrhythmia, viral myocarditis "second hits") could plausibly influence expressivity but have not been reported for TNNC1 carriers specifically.

Protective factors: None reported in the literature for TNNC1-associated DCM specifically.

Gene-environment interactions: Not established for CMD1Z; no CTD or GxE database entries specific to TNNC1-DCM were identified in this search.

3. Phenotypes

Clinical signs/symptoms (cardiac): | Phenotype | Suggested HPO term | Notes | |---|---|---| | Dilated cardiomyopathy | HP:0001644 | Core defining feature | | Reduced left ventricular ejection fraction | HP:0025168 | "Severely reduced" per OMIM clinical synopsis | | Congestive heart failure | HP:0001635 | Presenting feature in most reported cases | | Biventricular dysfunction | (map via HP:0001644 + right ventricular dysfunction term) | Explicitly noted — both ventricles affected, not left-only | | Cardiomegaly | HP:0001640 | Expected secondary structural finding | | Ventricular arrhythmia | HP:0004308 | Reported in some family members | | Sudden cardiac death | HP:0001645 | Documented in affected relatives (severe/lethal course) |

Phenotype characteristics: - Age of onset: Highly variable — from infancy/early childhood to as late as the fifth decade within the same kindred (per OMIM clinical synopsis for #611879). A 3-year-old boy (nephew of the original proband) required cardiac transplantation, illustrating a severe pediatric-onset presentation within the family. - Severity: Described as "severe reduction in cardiac function" — among the more aggressive genetic DCM subtypes reported. - Progression: Progressive, with disease course reported by Mogensen et al. as showing complete penetrance and high risk of premature death; the original paper's broader thesis (covering TNNC1 and TNNT2 mutation carriers together) was that troponin-gene DCM carries an adverse prognosis warranting early identification: "disease expression associated with TNNC1 and TNNT2 mutations was severe with complete penetrance" (PMID: 15542288). - Outcome burden: Most affected individuals in the literature required cardiac transplantation for survival. - Frequency among affected individuals: All reported carriers of the G159D mutation manifested disease (complete penetrance in the index family), though this is based on a single (small) kindred and should not be over-generalized as a population-level penetrance estimate.

Quality of life impact: Not separately quantified in TNNC1-specific literature; by extension from general severe pediatric/adult DCM with transplant dependence, substantial impact on functional status, growth (if pediatric-onset), and long-term quality of life would be expected, but no EQ-5D/SF-36 data specific to CMD1Z were located.

4. Genetic/Molecular Information

Causal gene: TNNC1 (HGNC:11940; OMIM *191040), encoding cardiac/slow-skeletal troponin C (cTnC), UniProt P63316.

Pathogenic variants: | Variant | Type | Classification | Notes | |---|---|---|---| | c.476G>A, p.Gly159Asp (G159D) | Missense | Pathogenic (ClinVar RCV000013254, OMIM-sourced, 0★) | Founder/index CMD1Z mutation; C-terminal domain, constitutively Ca²⁺-occupied site | | p.Tyr5His (Y5H) | Missense | Reported DCM-associated | Functionally characterized (Chung 2011) | | p.Met103Ile (M103I) | Missense | Reported DCM-associated | Decreased Ca²⁺ sensitivity of force development in vitro | | p.Asp145Glu (D145E) | Missense | Reported DCM-associated (also reported in HCM context in other cohorts) | Altered α-helical content on CD spectroscopy | | p.Ile148Val (I148V) | Missense | Reported DCM-associated | Altered α-helical content on CD spectroscopy | | p.Ala8Val (A8V) | Missense | Predominantly HCM/restrictive phenotype (CMH13), not CMD1Z | Included for contrast — illustrates TNNC1 phenotypic pleiotropy |

Zygosity: Heterozygous, autosomal dominant for the DCM phenotype (a compound-heterozygous TNNC1 presentation has also been separately reported in the DCM literature — "Familial Dilated Cardiomyopathy Associated With a Novel Combination of Compound Heterozygous TNNC1 Variants," Frontiers in Physiology 2019 — indicating rare biallelic/compound presentations exist alongside the classic dominant CMD1Z pattern).
Functional consequence — mechanistically complex, not simple loss-of-function:
G159D: impairs interaction of mutant cTnC with wild-type troponin T (decreased TnC–TnT binding) while enhancing interaction with troponin I — an altered, not simply reduced, regulatory interaction.
In skinned muscle fibers/explanted human myocardium, G159D produced a ~50% decrease in the rate of activation without significantly altering steady-state Ca²⁺ sensitivity or cooperativity of force generation (PMID: 17021793, Preston et al., Pflügers Arch 2007).
In intact skinned ventricular myocytes from an explanted G159D heart, Ca²⁺ sensitivity was higher than donor myocytes, and dephosphorylation-induced Ca²⁺-sensitivity changes normally seen with wild-type troponin were blunted in mutant troponin — leading to the proposed mechanism of "uncoupling of the relationship between troponin phosphorylation and myofilament Ca²⁺ sensitivity" as a driver of the DCM phenotype (PMID: 19808376, Dyer et al., Circ Heart Fail 2009; PMID: 17577574, Biochem Biophys Res Commun 2007).
Other TNNC1-DCM variants (Y5H, M103I) instead show decreased myofilament Ca²⁺ sensitivity of force development, and all four (Y5H, M103I, D145E, I148V) show reduced α-helical content by circular dichroism, indicating variant-specific structural destabilization (PMID: 21832052).
This heterogeneity — some variants desensitizing, some sensitizing myofilament Ca²⁺ response — parallels the broader troponin-cardiomyopathy literature in which DCM- and HCM-causing troponin/tropomyosin mutations have opposing effects on thin-filament Ca²⁺ affinity (Circulation Research, PMC3627712).
Allele frequency: Not found in 200 control chromosomes in the original description; specific gnomAD population allele frequency for G159D was not retrieved in this search and should be queried directly against gnomAD before curation (expected to be absent/extremely rare given pathogenicity and complete penetrance in the founder family).
Somatic vs. germline: Germline (inherited, autosomal dominant).
Epigenetics/chromosomal abnormalities: None reported — CMD1Z is a point-mutation (missense) disorder, not a copy-number or epigenetic disease.

5. Environmental Information

No specific environmental toxin, occupational exposure, or infectious trigger has been reported as causal or modifying for TNNC1/CMD1Z in the literature surveyed. No lifestyle-factor (diet, exercise, alcohol) association specific to TNNC1 carriers was identified. This section is not applicable / not established for CMD1Z beyond the generic considerations that apply to any DCM patient (e.g., avoidance of additional cardiotoxic stressors is standard clinical advice but is not disease-mechanism-specific).

6. Mechanism / Pathophysiology

Causal chain (from molecular lesion to clinical phenotype):

Trigger (molecular): Missense mutation in TNNC1 (e.g., G159D) alters the structure/protein-protein interaction surface of cardiac troponin C within the troponin complex on the thin filament.
Molecular dysfunction: Altered TnC–TnT and TnC–TnI binding (G159D: ↓TnT binding, ↑TnI binding); altered α-helical content/structural stability for other variants (Y5H, M103I, D145E, I148V); uncoupling of the normal relationship between troponin I phosphorylation (via PKA, a beta-adrenergic effector) and myofilament Ca²⁺ sensitivity.
Cellular/sarcomeric consequence: Abnormal Ca²⁺-dependent regulation of actin-myosin cross-bridge cycling — some variants increase resting/diastolic Ca²⁺ sensitivity (impairing relaxation and blunting the normal beta-adrenergic-driven desensitization needed for exercise/stress response), others decrease systolic force-generating Ca²⁺ sensitivity (directly impairing contractile force). Both routes converge on impaired, dysregulated myofilament contractile performance rather than a uniform "loss of function."
Tissue/organ consequence: Impaired sarcomere contractile efficiency across the myocardium → compensatory ventricular remodeling and progressive chamber dilation, biventricular systolic dysfunction, and reduced ejection fraction.
Clinical/organism-level consequence: Congestive heart failure, ventricular arrhythmia, and in severe cases sudden cardiac death or need for transplantation.

Molecular pathway / protein context: Cardiac troponin C is the Ca²⁺-sensing subunit of the troponin complex (TnC–TnI–TnT) on the thin filament, which in turn interacts with tropomyosin to gate myosin–actin interaction in a Ca²⁺-dependent manner (excitation–contraction coupling). This is the canonical cardiac muscle contraction pathway (GO: regulation of cardiac muscle contraction).

Cellular process: Sarcomeric/myofilament Ca²⁺-regulated contraction (not apoptosis- or inflammation-driven at the primary-lesion level, distinguishing this mechanistically from e.g. BAG3-related DCM, which involves proteostasis/Z-disc/apoptosis pathways).

Protein dysfunction category: Altered protein–protein interaction and reduced structural stability (not simple loss-of-function or aggregation); a dominant-negative/altered-function mechanism is implicated by the enhanced-TnI-binding/decreased-TnT-binding pattern and blunted phosphorylation response, consistent with autosomal dominant inheritance with a single mutant allele exerting effects within the assembled troponin complex.

Suggested GO terms (biological process/molecular function/cellular component): - GO:0006936 muscle contraction - GO:0055117 regulation of cardiac muscle contraction - GO:0005509 calcium ion binding - GO:0031014 troponin C binding (or GO:0030172 troponin binding, verify exact term) - GO:0005861 troponin complex (cellular component) - GO:0030017 sarcomere (cellular component)

Suggested CL term: CL:0000746 cardiac muscle cell (myocyte).

Suggested UBERON terms: UBERON:0000948 heart; UBERON:0002084 heart left ventricle; UBERON:0002078 heart right ventricle; UBERON:0002349 myocardium.

Suggested CHEBI term: CHEBI:29108 calcium(2+).

(All ontology term suggestions above should be independently verified via OAK/runoak info before insertion into KB YAML per dismech's anti-hallucination policy — several are plausible-but-unverified in this research pass.)

Molecular profiling / advanced technologies: No transcriptomic, proteomic, metabolomic, single-cell, or spatial-transcriptomic datasets specific to TNNC1-CMD1Z human myocardium were identified in this search. Biophysical/functional characterization (skinned-fiber mechanics, circular dichroism, mass spectrometry of expressed mutant protein) constitutes the primary "omics-adjacent" evidence base, performed in explanted patient myocardium and reconstituted/recombinant protein systems (in vitro, IN_VITRO evidence class) plus knock-in mouse models (MODEL_ORGANISM evidence class, see Section 15).

7. Anatomical Structures Affected

Primary organ: Heart (biventricular — both left and right ventricles affected, an important distinguishing clinical feature noted in the OMIM clinical synopsis).
Secondary/systemic involvement: Congestive heart failure sequelae (pulmonary congestion, hepatic congestion) as downstream complications of pump failure; no primary extracardiac organ involvement is described (TNNC1's cardiac isoform is the relevant one for this phenotype — TNNC1 is also expressed in slow skeletal muscle, but no associated skeletal myopathy phenotype is reported for CMD1Z).
Body system: Cardiovascular system (isolated, non-syndromic).
Tissue level: Cardiac (striated) muscle tissue — specifically the sarcomere/myofibril of cardiomyocytes.
Cell level: Cardiomyocytes (ventricular myocytes of both chambers).
Subcellular level: Sarcomere thin filament / troponin complex (GO Cellular Component: troponin complex, thin filament).
Laterality: Bilateral/biventricular — not unilateral.

8. Temporal Development

Onset: Highly variable within the same family — ranges from infancy/early childhood to the fifth decade of life. No single modal onset age is established; this wide intrafamilial variability is itself a notable feature of the OMIM clinical synopsis.
Onset pattern: Can present acutely with heart failure or be identified via family cascade screening in an initially asymptomatic carrier; disease course once manifest is progressive.
Progression: Progressive systolic dysfunction; described as "severe" with complete penetrance in the index family, culminating in transplant-level heart failure in multiple reported individuals.
Disease course pattern: Chronic, progressive (not episodic/relapsing-remitting) — consistent with structural/sarcomeric DCM generally, in contrast to arrhythmia-first channelopathies.
Duration: Chronic, lifelong once manifest; not self-limited.
Remission: No spontaneous remission reported; standard heart-failure therapy can produce partial functional improvement (as in any GDMT-responsive DCM) but no TNNC1-specific reverse-remodeling data were found.
Critical periods: Early genetic diagnosis via family cascade screening is emphasized in the founding literature as clinically important given the "adverse prognosis and high risk of premature death" associated with troponin-gene DCM (PMID: 15542288) — i.e., the actionable window is pre-symptomatic identification of at-risk relatives.

9. Inheritance and Population

Epidemiology: - TNNC1-specific prevalence/incidence: Not separately quantified in disease registries; CMD1Z is an ultra-rare DCM subtype. TNNC1 mutations account for only a small fraction of genotyped familial DCM cases (troponin-complex genes collectively represent a minority of the ~30–40 known DCM genes, with TNNC1 being one of the rarer contributors, based on original identification in a single large kindred plus scattered subsequent case reports). - General DCM epidemiology (context): Overall DCM prevalence estimates range from ~1:250 (broader/CMR-based estimates) to 1:2,500 in older estimates, with incidence of ~5–7 cases per 100,000 person-years; ~30–50% of cases are familial, and a genetic cause is identifiable in ~35–40% of cases overall (Nature Reviews Cardiology, PMC4288017, PMC12393173).

Inheritance pattern: Autosomal dominant, based on heterozygous mutation transmission and multi-generational pedigree segregation in the founding CMD1Z family (a rare compound-heterozygous presentation has also been separately reported, suggesting biallelic modes can occur atypically).

Penetrance: Complete penetrance reported in the index G159D family — all mutation carriers manifested disease — though this is based on one kindred and should not be treated as a population-wide certainty.

Expressivity: Highly variable — age of onset spans from infancy to the fifth decade within the same family, and severity ranges from milder disease to transplant-requiring heart failure in early childhood, indicating substantial variable expressivity even among carriers of the identical G159D variant.

Genetic anticipation: Not reported/not applicable (TNNC1-DCM is not a repeat-expansion disorder).

Germline mosaicism: Not specifically reported for TNNC1.

Founder effects: The G159D mutation was identified in a single large kindred (Family A); whether it represents a true founder mutation recurring in additional unrelated families, or is private to this pedigree, was not established in the sources reviewed.

Consanguinity: Not implicated — autosomal dominant inheritance from a single mutant allele does not require consanguinity (contrast with the unrelated TNNC1-A8V homozygous restrictive-cardiomyopathy phenotype in infants, which does involve homozygosity, but that maps to a different, non-CMD1Z phenotype).

Carrier frequency: Not established; expected to be extremely low given the rarity/private nature of reported variants.

Population demographics: No specific ethnic, geographic, or sex-ratio data specific to CMD1Z/TNNC1 carriers were identified (contrast with general DCM, which shows a male predominance of roughly 2:1 in some population-based imaging studies).

10. Diagnostics

Clinical/functional tests: - Echocardiography / cardiac MRI: Standard imaging to document left (and right) ventricular dilation and reduced ejection fraction — the core diagnostic modality for the DCM phenotype itself. - ECG: May show nonspecific abnormalities and, per the mouse-model literature (Section 15), prolonged QRS/QT can accompany TnC-mutation cardiomyopathy, relevant to arrhythmia risk stratification. - Endomyocardial biopsy / explanted myocardium: Used in the primary research literature (not routine clinical diagnosis) to perform functional/biophysical characterization of mutant troponin (skinned-fiber mechanics, myocyte Ca²⁺-sensitivity assays).

Genetic testing: - Recommended approach: Given TNNC1's status as one of dozens of established DCM genes, multigene DCM panel testing (including TNNC1 alongside TTN, LMNA, MYH7, TNNT2, TPM1, SCN5A, RBM20, BAG3, DES, PLN, FLNC, etc.) is the standard first-tier genetic test, per current DCM genetic-testing practice, rather than single-gene TNNC1 sequencing as a first step (unless a familial variant is already known, in which case targeted single-gene/site testing is appropriate for cascade screening). - Whole exome/genome sequencing: Useful when panel testing is uninformative or phenotype is atypical/syndromic. - Cascade family screening: Emphasized in the founding literature as clinically important — once a pathogenic TNNC1 variant is identified in a proband, targeted testing of at-risk relatives is indicated given complete penetrance and "high risk of premature death" in the index family. - Chromosomal microarray/karyotype/FISH: Not indicated — CMD1Z is a single-gene missense disorder, not a chromosomal disorder. - Mitochondrial DNA testing: Not applicable.

Clinical criteria: Standard DCM diagnostic criteria (echocardiographic LV dilation + systolic dysfunction not explained by ischemic, valvular, or hypertensive disease) apply; TNNC1/CMD1Z is distinguished from other DCM etiologies purely by molecular genetic testing, not by distinctive clinical/imaging features.

Differential diagnosis: Other genetic DCM subtypes (TTN-truncating variants — the single most common identifiable cause of genetic DCM; LMNA-associated DCM with conduction disease; other troponin/sarcomeric-gene DCM such as TNNT2; BAG3-associated DCM); acquired DCM causes (ischemic, viral/myocarditis, alcohol-related, peripartum, tachycardia-induced) must be excluded clinically before/alongside genetic workup.

Screening: No population-based newborn screening program exists for TNNC1/CMD1Z (as with virtually all monogenic cardiomyopathies); the relevant screening paradigm is genetic cascade screening of first-degree relatives of a known proband.

11. Outcome/Prognosis

Prognosis: Described in the founding literature as "severe... with complete penetrance," with mutation analysis proposed as valuable for "early identification of individuals with an adverse prognosis and a high risk of premature death" (PMID: 15542288) — i.e., TNNC1 (and TNNT2) mutation-associated DCM was specifically flagged as carrying a worse prognosis than DCM overall.
Transplantation burden: Multiple reported individuals, including a child as young as 3 years old, required cardiac transplantation, indicating that end-stage heart failure requiring transplant is a realistic outcome trajectory for this subtype, not a rare tail event.
Mortality: No TNNC1-specific quantitative survival statistics (e.g., 5-/10-year survival rates) were located in this search; general severe pediatric/familial DCM carries substantial mortality/transplant risk without intervention, consistent with the qualitative "adverse prognosis" language used for this gene.
Complications: Congestive heart failure, ventricular arrhythmia, sudden cardiac death (documented in family members), and transplant-related complications for those who progress to transplantation.
Prognostic factors: Genotype itself (TNNC1/TNNT2 mutation carrier status) was proposed by Mogensen et al. as a prognostic marker justifying early genetic identification — i.e., this is one of the earliest examples in the DCM literature of genotype-based risk stratification informing clinical management recommendations.

12. Treatment

No TNNC1/CMD1Z-specific, genotype-targeted therapy exists. Management follows standard guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction, applied to this genetic DCM subtype as to DCM generally:

Pharmacotherapy (NCIT:C15986 Pharmacotherapy): - ACE inhibitors / ARBs / angiotensin receptor–neprilysin inhibitors (ARNI) - Beta-blockers - Mineralocorticoid receptor antagonists (MRAs) - SGLT2 inhibitors (contemporary "quadruple therapy" per 2022 ACC/AHA/HFSA and ESC guidelines)

Device therapy: - Implantable cardioverter-defibrillator (ICD): Class I recommendation for non-ischemic DCM with NYHA class II–III symptoms and LVEF ≤35% on optimal medical therapy (relevant given the documented ventricular arrhythmia/sudden death risk in CMD1Z families) — though the evidence base for ICD mortality benefit specifically in non-ischemic cardiomyopathy is debated (the DANISH trial did not show an overall mortality benefit). - Cardiac resynchronization therapy (CRT): Indicated for persistent systolic dysfunction with significant intraventricular conduction delay.

Surgical/advanced: - Heart transplantation (NCIT:C15289 Organ Transplantation): The definitive intervention for refractory disease — explicitly documented as required in multiple reported CMD1Z family members, including pediatric cases. - Mechanical circulatory support (e.g., LVAD) as a bridge to transplant or destination therapy in critically ill patients who cannot be stabilized medically.

Genetic counseling (NCIT:C15240 Genetic Counseling): Recommended given autosomal dominant inheritance, complete penetrance in the index family, and the prognostic significance of genotype — supports cascade testing of at-risk relatives.

Experimental/targeted therapy: No TNNC1-targeted small-molecule, gene-therapy, or myofilament-modulating agent specific to this variant class was identified in this search (in contrast to some other genetic cardiomyopathies where myosin modulators are in active development). This remains an open area — no ClinicalTrials.gov entries specific to TNNC1-DCM were surfaced.

13. Prevention

Primary prevention: Not applicable in the traditional sense (a genetic, inherited structural mutation cannot be prevented); the closest analog is reproductive genetic counseling / preimplantation genetic diagnosis for known carrier families wishing to avoid transmission.
Secondary prevention: Cascade genetic screening of at-risk first-degree relatives of a proband, enabling pre-symptomatic identification and early initiation of surveillance (serial echocardiography) and, if dysfunction emerges, early GDMT — directly supported by the founding literature's emphasis on early identification given adverse prognosis.
Tertiary prevention: Standard heart-failure GDMT and device therapy (as above) to reduce progression to end-stage disease, arrhythmic death, and transplant need in those already diagnosed.
Immunization/public health/prophylaxis: Not applicable — this is not an infectious or environmentally preventable disease.

14. Other Species / Natural Disease

No naturally occurring TNNC1-associated dilated cardiomyopathy in companion animals or wildlife was identified in this search (no OMIA entry surfaced). TNNC1 orthologs are highly conserved across vertebrates (troponin C is a core, evolutionarily ancient sarcomeric protein), making cross-species mechanistic conservation plausible, but no veterinary natural-disease case reports specific to this gene were found in the sources reviewed. This section should be treated as not established / no data found for CMD1Z specifically, pending a dedicated OMIA/veterinary-literature search.

15. Model Organisms

Mouse knock-in model (a related Ca²⁺-desensitizing TNNC1 mutation, D73N): Heterozygous D73N (+/–) knock-in mice — D73N lies in the regulatory N-domain's second Ca²⁺-binding loop of cardiac troponin C — develop early-onset dilated cardiomyopathy: mice began dying at 6 weeks of age, with median survival of 12 weeks; echocardiography showed ejection fraction reduced to ~28% (vs. ~69% wild-type) and fractional shortening to ~13% (vs. ~38% wild-type), with LV dilation, wall thinning, increased heart-weight/body-weight ratio, prolonged QRS/QT intervals, ~2.4-fold increase in β-myosin heavy chain (a molecular heart-failure marker), and loss of ventricular myocyte responsiveness to β-adrenergic stimulation (PMID: 26379556, Frontiers in Physiology 2015). Mechanistically, D73N increases the rate of Ca²⁺ dissociation from the regulatory domain, reducing myofilament Ca²⁺ sensitivity and impairing systolic function — directly recapitulating the human sarcomeric-DCM paradigm of impaired Ca²⁺-myofilament coupling, and providing an in vivo model for the general class of Ca²⁺-desensitizing TNNC1 mutations to which CMD1Z belongs (note: this is a distinct residue from the CMD1Z-defining G159D variant — no G159D-specific knock-in mouse model was identified in this search).
Reconstituted/recombinant protein systems (in vitro): Recombinant mutant human cTnC (G159D, Y5H, M103I, D145E, I148V) reconstituted into TnC-depleted porcine cardiac/papillary skinned muscle fibers is the principal functional model system used to characterize Ca²⁺-sensitivity and force-generation effects of individual CMD1Z-associated variants (PMID: 21832052; PMID: 17021793).
Ex vivo human tissue: Explanted failing human myocardium from a G159D-mutation carrier undergoing transplantation was directly studied (skinned myocyte force–Ca²⁺ relationships, troponin phosphorylation assays), providing a direct human-tissue functional correlate rather than relying solely on heterologous/animal systems (PMID: 19808376).
Model limitations: The D73N mouse model, while mechanistically informative for the Ca²⁺-desensitization paradigm, is not genotype-matched to the G159D CMD1Z-defining mutation — a curatorial HUMAN_MODEL_MISMATCH-type caveat is warranted if this model is cited as direct support for CMD1Z pathophysiology specifically, since G159D's own functional profile (increased, not decreased, Ca²⁺ sensitivity in human myocytes; altered phosphorylation-coupling rather than straightforward desensitization) differs mechanistically from D73N.

Summary Table — Key Curation-Ready Facts

Field	Value	Primary source
Disease	Dilated Cardiomyopathy 1Z (CMD1Z)	OMIM #611879
Gene	TNNC1 (cardiac troponin C)	OMIM *191040
Locus	3p21.1	OMIM
Inheritance	Autosomal dominant (complete penetrance in index family)	Mogensen 2004, PMID 15542288
Founder variant	c.476G>A, p.Gly159Asp (G159D)	ClinVar RCV000013254; PMID 15542288
Other DCM-associated TNNC1 variants	Y5H, M103I, D145E, I148V	PMID 21832052
Onset	Infancy–5th decade (variable)	OMIM clinical synopsis
Key mechanism	Altered TnC–TnT/TnI binding; uncoupled troponin-phosphorylation/Ca²⁺-sensitivity relationship; variant-dependent Ca²⁺ sensitization or desensitization	PMID 19808376, 17021793, 17577574, 21832052
Severity/prognosis	Severe, adverse prognosis, high risk of premature death, transplant frequently required	PMID 15542288
Treatment	Standard HFrEF GDMT, ICD/CRT, transplantation	General DCM guidelines (ACC/AHA/HFSA 2022; ESC 2023)
Mouse model (related variant)	D73N knock-in — 6-wk onset, 12-wk median survival, EF ~28%	PMID 26379556

Notes on Evidence Quality / Curation Caveats

The CMD1Z literature base is thin and centers on one large founding kindred plus a handful of subsequent variant reports — treat prevalence/penetrance figures as pedigree-specific, not population-validated.
The ClinVar classification for G159D carries 0-star review status (single OMIM-sourced submission, no independent multi-lab ACMG/AMP assertion) — flag as needing contemporary reclassification confirmation before treating as definitively "Pathogenic" in a modern curation context.
No MONDO ID specific to CMD1Z was confirmed in this pass — verify directly against the MONDO ontology rather than assuming absence.
OMIM's own full clinical-synopsis text could not be directly fetched (403 response) — the clinical details above were triangulated from search-engine-summarized OMIM content and secondary sources; direct OMIM API/text confirmation is recommended before final KB entry.
The mouse model cited (D73N) is mechanistically related but not variant-matched to the CMD1Z-defining G159D mutation — this should be modeled as a HUMAN_MODEL_MISMATCH-style caveat if incorporated into a dismech entry, per project convention.

Sources: - OMIM #611879 — CARDIOMYOPATHY, DILATED, 1Z; CMD1Z - OMIM *191040 — TROPONIN C, SLOW; TNNC1 - Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy — PubMed (PMID 15542288) - Functional characterization of TNNC1 rare variants identified in dilated cardiomyopathy — PubMed (PMID 21832052) - Functional effects of the DCM mutant Gly159Asp troponin C in skinned muscle fibres — PubMed (PMID 17021793) - DCM troponin C mutant Gly159Asp blunts the response to troponin phosphorylation — PubMed (PMID 17577574) - Functional Analysis of a Unique Troponin C Mutation, GLY159ASP... Studied in Explanted Heart Muscle — Circulation: Heart Failure (PMID 19808376) - NM_003280.3(TNNC1):c.476G>A (p.Gly159Asp) AND Dilated cardiomyopathy 1Z — ClinVar - Knock-in mice harboring a Ca2+ desensitizing mutation in cardiac troponin C develop early onset dilated cardiomyopathy — PMC (PMID 26379556) - Orphanet: TNNC1 — troponin C1, slow skeletal and cardiac type - Familial Dilated Cardiomyopathy Associated With a Novel Combination of Compound Heterozygous TNNC1 Variants — Frontiers in Physiology - Epidemiology of the inherited cardiomyopathies — Nature Reviews Cardiology - GENETIC CAUSES OF DILATED CARDIOMYOPATHY — PMC (PMC4288017) - Dilated Cardiomyopathy (DCM) Guidelines — 2022 ACC/AHA/HFSA, 2023 ESC — Medscape - Current Management and Treatment — Dilated Cardiomyopathy — NCBI Bookshelf - NM_003280.3(TNNC1):c.23C>T (p.Ala8Val) AND Hypertrophic cardiomyopathy 13 — ClinVar

Dilated Cardiomyopathy 1Z

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Dilated Cardiomyopathy 1Z (CMD1Z) — Comprehensive Research Report

1. Disease Information

2. Etiology

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4. Genetic/Molecular Information

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6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

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