Submissions for variant NM_003280.3(TNNC1):c.23C>T (p.Ala8Val)

gnomAD frequency: 0.00001  dbSNP: rs267607125

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000824773	SCV000061424	likely pathogenic	Hypertrophic cardiomyopathy	2018-03-16	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000159204	SCV000209150	likely pathogenic	not provided	2025-02-20	criteria provided, single submitter	clinical testing	Identified in patients with hypertrophic cardiomyopathy and restrictive cardiomyopathy referred for genetic testing at GeneDx and in published literature (PMID: 27574918, 18572189, 27604170, 35769956, 28771489, 24793961, 30775854); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22489623, 27604170, 33407484, 23425245, 19439414, 21056975, 20459070, 26183555, 26304555, 28473771, 28445763, 28049727, 28533433, 30138628, 30070845, 24744096, 26529187, 27721798, 34488226, 33179204, 33658040, 30847666, 35838319, 36264615, 26976709, 27574918, 28771489, 35769956, 24793961, 30775854, 18572189)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001034686	SCV000648283	pathogenic	Dilated cardiomyopathy 1Z; Hypertrophic cardiomyopathy 13	2024-10-07	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 8 of the TNNC1 protein (p.Ala8Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with hypertrophic cardiomyopathy and/or TNNC1-related conditions (PMID: 18572189, 27574918, 30775854, 30847666, 33658040; internal data). ClinVar contains an entry for this variant (Variation ID: 12443). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects TNNC1 function (PMID: 18572189, 19439414, 20459070, 21056975, 22489623, 23425245, 26304555). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000618084	SCV000740104	likely pathogenic	Cardiovascular phenotype	2023-01-19	criteria provided, single submitter	clinical testing	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.
CeGaT Center for Human Genetics Tuebingen	RCV000159204	SCV001246948	likely pathogenic	not provided	2022-08-01	criteria provided, single submitter	clinical testing	TNNC1: PM2, PS4:Moderate, PP3, PS3:Supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001582477	SCV001821228	likely pathogenic	Cardiomyopathy	2023-11-20	criteria provided, single submitter	clinical testing	Variant summary: TNNC1 c.23C>T (p.Ala8Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. As this variant is located in the exonic splice region close to the canonical intronic splice donor site, several computational tools predict a conflicting impact on normal splicing: One predicts no significant impact on splicing. One predicts the variant abolishes the canonical 5' splicing donor site. Two predict the variant weakens the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.3e-05 in 1585600 control chromosomes (gnomAD v4.0). This frequency is not significantly higher than estimated for a pathogenic variant in TNNC1 causing Cardiomyopathy (1.3e-05 vs 2.5e-05), allowing no conclusion about variant significance. c.23C>T has been reported in the literature in individuals affected with Cardiomyopathy (eg. Landstrom_2008, Bos_2014, Jaafar_2015, Martins_2015, Ploski_2016, Jaaskelainen_2019, Mademont-Soler_2017, van Lint_2019, etc). The only segregation data reported by these studies was the observation of the variant in two siblings with infantile onset restrictive cardiomyopathy who were compound heterozygous with a second variant in TNNC1, and both heterozygous parents were asymptomatic (Ploski_2016). These data indicate that the variant is very likely to be associated with disease. There have been a variety of in vitro functional studies reported on this variant which suggest the variant 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 (eg. Landstrom_2008). Additionally, a mouse model with this variant was shown to recapitulate aspects of human HCM, further suggesting a functional impact of the variant (Martins_TNNC1_CCG_2015). The following publications have been ascertained in the context of this evaluation (PMID: 24793961, 26779504, 30775854, 18572189, 28771489, 26304555, 27604170, 30847666). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (P/LP, n=9 ; VUS, n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001582477	SCV002043226	likely pathogenic	Cardiomyopathy	2019-10-10	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001034686	SCV002811491	likely pathogenic	Dilated cardiomyopathy 1Z; Hypertrophic cardiomyopathy 13	2021-08-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147283	SCV003835266	pathogenic	Dilated cardiomyopathy 1Z	2022-06-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000013256	SCV003835274	pathogenic	Hypertrophic cardiomyopathy 13	2022-06-28	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000013256	SCV003841812	pathogenic	Hypertrophic cardiomyopathy 13	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 18572189). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.73; 3Cnet: 0.88). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012443). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
OMIM	RCV000013256	SCV000033503	pathogenic	Hypertrophic cardiomyopathy 13	2008-08-01	no assertion criteria provided	literature only
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000037762	SCV000280500	uncertain significance	not specified	2015-01-21	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Ala8Val (c. 23 C>T) in TNNC1 Given the lack of case data and the somewhat tenuous link between HCM and TNNC1, we classify it as a variant of uncertain significance. This variant has been reported in one individual with HCM; he was diagnosed at 33 and had no family history of SCD or HCM (Landstrom et al 2008). To the best of our knowledge there are no other published reports of this variant in HCM. There is also no segregation data available on this variant. Only a handful of variants in TNNC1 have been reported in association with HCM and some groups question whether there is sufficient evidence supporting the link between HCM and TNNC1. Interestingly, from the paper that first reported this variant we are able to get data on the prevalence of TNNC1 variants in patients with HCM, which we can then compare to the prevalence of such variants in the general population. Landstrom et al (2008) sequenced TNNC1 in 1025 patients with HCM and identified rare missense variants (including this one) in 4 individuals (i.e. ~0.4%). Of note, in a general population sample, 0.1% of individuals had a rare or unique missense variant in TNNC1 (from the NHLBI ESP data set). Landstrom et al (2008) showed that specific missense mutations occurring in TNNC1, including this p.Ala8Val variant, show increased Ca2+ sensitivity of force development and force recovery. However, a subsequent paper from the same group noted that this variant was associated with diminished Ca2+ sensitivity (Pinto et al 2009). Swindle et al (2010) reported that p.Ala8Val did not affect the calcium or magnesium binding properties of the C-domain and it had no effects on binding of troponin C to troponin I. This variant occurs in the N-helix of the amino acid-terminal domain of the protein. The Alanine at codon 8 is completely conserved (Landstrom et al 2008). PolyPhen2 predicts the variant to be possibly damaging. It is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~5,300 Caucasian and African American individuals (as of May 2012). It is also not currently listed in dbSNP or 1000 genomes (as of May 2012). Landstrom et al (2008) did not observe the variant in 500 general population samples. p. Asp464Asn (c. 1390 G>A) in PRKAG2 Genetic testing also identified another variant of unknown significance in the PRKAG2 gene, Asp464Asn (c. 1390 G>A). This variant is novel. This results in a non-conservative amino acid change, where a negatively-charged amino acid (Aspartic Acid) is changed to a neutral, polar amino acid (Asparagine). This variant is predicted to be benign by PolyPhen-2 analysis. This residue is conserved across species. No other disease-causing variants have been reported at this or nearby codons. The variant was not observed in 313 individuals of various ethnic backgrounds at GeneDx. The variant is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~5,000 Caucasian and African American individuals (as of May 2012). The variant is not listed in dbSNP or 1000 genomes (as of May 2012).
Clinical Genetics, Academic Medical Center	RCV000159204	SCV001920970	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000159204	SCV001951874	pathogenic	not provided		no assertion criteria provided	clinical testing