ClinVar

Description

The p.A8V variant (also known as c.23C>T), located in coding exon 1 of the TNNC1 gene, results from a C to T substitution at nucleotide position 23. The alanine at codon 8 is replaced by valine, an amino acid with similar properties. This alteration has been detected in numerous individuals with hypertrophic cardiomyopathy (HCM) (Landstrom AP et al. J Mol Cell Cardiol. 2008;45:281-8; Jaafar N et al. Glob Cardiol Sci Pract. 2015;2015:16; Mademont-Soler I et al. PLoS ONE, 2017 Aug;12:e0181465; GeneDx pers. comm; Invitae pers. comm.; Ambry internal data). This alteration was also detected in siblings with early onset restrictive cardiomyopathy (RCM) who both carried a second alteration in the TNNC1 gene (Ploski R et al. Am J Med Genet A., 2016;170:3241-3248). This alteration was also reported in an infant with microcephaly and RCM (Elmas M et al. J Pediatr Genet, 2022 Jun;11:110-116). A variety of in vitro functional studies have suggested that this alteration impacts the function of the Troponin C protein, but the observed effects were varied and the physiological relevance of those effects in humans is unclear (Landstrom AP et al. J Mol Cell Cardiol. 2008;45:281-8; Pinto JR et al. J Biol Chem. 2009;284:19090-100; Swindle N et al. Biochemistry. 2010;49:4813-20; Pinto JR et al. J Biol Chem. 2011;286:1005-13; Albury AN et al. Biochemistry. 2012;51:3614-21; Cordina NM et al. Biochemistry. 2013;52:1950-62; Zot HG et al. Arch Biochem Biophys. 201;601:97-104). However, aspects of human HCM are recapitulated in a mouse model with this alteration (Martins AS et al. Circ Cardiovasc Genet. 2015;8:653-64). This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.