Submissions for variant NM_001276345.2(TNNT2):c.341C>T (p.Ala114Val)

gnomAD frequency: 0.00002  dbSNP: rs727504245

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154215	SCV000203868	uncertain significance	not specified	2017-08-15	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Ala104Val variant in TNNT2 has been identified in 4 individuals with HCM (Nakajima-Tanigu chi 1997, Pasquale 2012, LMM data). It has also been identified in 1/8654 East A sian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadins titute.org; dbSNP rs727504245). In vitro functional studies provide some evidenc e that the p.Ala104Val variant may impact protein function (Palm 2001, Harada 20 04). However, these types of assays may not accurately represent biological func tion. This variant was also predicted to be pathogenic using a computational too l clinically validated by our laboratory. This tool's pathogenic prediction is e stimated to be correct 94% of the time (Jordan 2011). In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Ala104 Val variant is uncertain.
Invitae	RCV000476946	SCV000541918	pathogenic	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2024-01-28	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 104 of the TNNT2 protein (p.Ala104Val). This variant is present in population databases (rs727504245, gnomAD 0.006%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 9140840, 23396983, 27532257, 28790153, 31737537, 33297573; Invitae). This variant is also known as Ala114Val. ClinVar contains an entry for this variant (Variation ID: 177633). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TNNT2 protein function with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TNNT2 function (PMID: 11606294, 14722098, 33025817). For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000845306	SCV000987347	likely pathogenic	Primary familial hypertrophic cardiomyopathy		criteria provided, single submitter	clinical testing
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000853450	SCV000996361	uncertain significance	Hypertrophic cardiomyopathy	2017-04-19	criteria provided, single submitter	research	TNNT2 Ala104Val has been previously reported in a number of HCM cases, however to-date no familial segregation has been noted (LMM, personal communication; Walsh R et al., 2017; Lopes LR, et al., 2013; Pasquale F, et al., 2012; Nakajima-Taniguchi C, et al., 1997). In vitro functional assays suggest that the variant alters tropomyosin binding (Hinkle A & Tobacman LS, 2002) and calcium sensitivity (Harada K & Potter JD, 2004), however this may not necessarily translate to altered protein function in vivo. The variant is present as a singleton event in Exome Aggregation Consortium dataset (MAF=0.000008; http://exac.broadinstitute.org/). We identified this variant in a HCM proband of Middle Eastern descent. The proband has no family history of disease or sudden cardiac death. Computational tools SIFT, PolyPhen-HCM and PolyPhen-2 predict this variant to have a deleterious effect, however MutationTaster predicts this variant to be a "polymorphism". In summary, based on reports in several HCM probands, as well as rarity in the general population and some evidence of altered protein function in functional assays, we classify TNNT2 Ala104Val as a variant of "uncertain significance"
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001171166	SCV001333855	uncertain significance	Cardiomyopathy	2018-03-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001171166	SCV001350178	uncertain significance	Cardiomyopathy	2023-05-26	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 104 in the tropomyosin binding domain 1 of the TNNT2 protein. This variant is also known as c.341C>T, p.Ala114Val based on transcript NM_000364.4. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that the mutant protein binds to tropomyosin (TPM1) normally, although it may be less effective than wild type in promoting tropomyosin binding to actin (PMID: 11606294). It has also been shown that the variant does not significantly change maximum isometric force development or Ca2+ sensitivity (PMID: 14722098). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 9140840, 23396983, 28408708, 27532257, 28790153, 33297573; DOI:10.13362/j.jpmed.202001002; communication with an external laboratory; ClinVar SCV000541918.9) and in an individual suspected to be affected with hypertrophic cardiomyopathy (PMID: 31737537). However, three of these individuals also carried a pathogenic variant in the MYH7 or MYBPC3 gene (PMID: 23396983), suggesting that this TNNT2 variant may not have been the primary cause of disease in these individuals. This variant has been identified in 4/251490 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197200	SCV001367837	uncertain significance	Dilated cardiomyopathy 1D	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PP2,PP3.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV002255095	SCV002037158	uncertain significance	Hypertrophic cardiomyopathy 2		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002321633	SCV002607481	uncertain significance	Cardiovascular phenotype	2023-06-21	criteria provided, single submitter	clinical testing	The p.A104V variant (also known as c.311C>T), located in coding exon 8 of the TNNT2 gene, results from a C to T substitution at nucleotide position 311. The alanine at codon 104 is replaced by valine, an amino acid with similar properties. This variant has been detected in an individual with hypertrophic cardiomyopathy (HCM) and family history of HCM and sudden death; however, gene analysis may have been limited (Nakajima-Taniguchi C et al. J. Mol. Cell. Cardiol. 1997 Feb;29(2):839-43). This variant (also referred to as p.A114V) has also been detected in additional HCM cohorts or cohorts referred for HCM genetic testing; however, in several cases, clinical detail or gene analysis was limited or the variant co-occurred with pathogenic mutations in other cardiomyopathy-associated genes. In addition, some reported cases may overlap (Pasquale F et al. Circ Cardiovasc Genet. 2012 Feb;5(1):10-7; Lopes LR et al. J Med Genet. 2013 Apr;50(4):228-39; Ingles J et al. Circ Cardiovasc Genet. 2017 Apr;10(2); Walsh R et al. Genet. Med. 2017 02;19(2):192-203; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298; Micheu MM et al. Diagnostics (Basel), 2020 Dec;10(12); Gorzynski JE et al. N Engl J Med. 2022 Feb;386(7):700-702). In vitro studies indicate this variant may alter some aspects of protein function; however, the physiological relevance of the findings is unclear (Palm T et al. Biophys. J. 2001 Nov;81(5):2827-37; Harada K et al. J. Biol. Chem. 2004 Apr;279(15):14488-95). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Clinical Genetics, Academic Medical Center	RCV001699043	SCV001917273	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001699043	SCV001953717	uncertain significance	not provided		no assertion criteria provided	clinical testing