TNNC1 – Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disorder characterized by unexplained left ventricular hypertrophy and predisposition to arrhythmia and sudden death. TNNC1 encodes cardiac troponin C (cTnC), the Ca²⁺-binding subunit of the troponin complex that regulates myofilament contraction. Although most HCM is caused by variants in thick-filament genes, TNNC1 variants account for a small but clinically important subset of cases.

1. Clinical Validity

The association between TNNC1 and HCM is categorized as Moderate by ClinGen, based on 4 unrelated probands with novel TNNC1 missense variants identified in a cohort of 1 025 HCM patients ([PMID:18572189]). Functional studies and an in vivo knock-in model provide concordant mechanistic data supporting pathogenicity.

2. Genetic Evidence

Inheritance is autosomal dominant. In a multicenter screen of 1 025 unrelated HCM patients, novel TNNC1 missense variants (Ala8Val, Cys84Tyr, Glu134Asp, Asp145Glu) were found at ~0.4% frequency ([PMID:18572189]). A de novo c.91G>T (p.Ala31Ser) was reported in a pediatric proband with ventricular fibrillation and aborted sudden cardiac death, diagnosed at age 5 with no family history ([PMID:22815480]). No additional segregating family members have been described.

3. Functional Evidence

Reconstituted skinned fibers containing cTnC-A31S or cTnC-A8V exhibit increased Ca²⁺ sensitivity of force development and actomyosin ATPase activity without global structural changes. Knock-in mice heterozygous for A8V display ventricular wall thickening, diastolic dysfunction, atrial enlargement, fibrosis, and dose-dependent increases in myofilament Ca²⁺ sensitivity ([PMID:26304555]).

4. Mechanism of Pathogenicity

HCM-associated TNNC1 variants enhance Ca²⁺ binding and sensitize the thin filament, altering excitation-contraction coupling. These changes likely promote maladaptive hypertrophy and arrhythmogenesis by disrupting normal Ca²⁺ handling and sarcomeric relaxation.

5. Conclusion

Heterozygous TNNC1 missense variants cause autosomal dominant HCM through a gain-of-function mechanism that increases myofilament Ca²⁺ sensitivity. While clinical cases are few, strong functional and animal model data support TNNC1 inclusion in diagnostic panels. Key take-home: TNNC1 should be screened in HCM genetic testing to inform risk stratification and management.

References

• Journal of molecular and cellular cardiology • 2008 • Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C. [PMID:18572189]
• Circulation. Cardiovascular genetics • 2015 • In Vivo Analysis of Troponin C Knock-In (A8V) Mice: Evidence that TNNC1 Is a Hypertrophic Cardiomyopathy Susceptibility Gene. [PMID:26304555]
• The Journal of biological chemistry • 2012 • A mutation in TNNC1-encoded cardiac troponin C, TNNC1-A31S, predisposes to hypertrophic cardiomyopathy and ventricular fibrillation. [PMID:22815480]

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