ClinVar Miner

Submissions for variant NM_001276345.2(TNNT2):c.341C>T (p.Ala114Val) (rs727504245)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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; 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 likely pathogenic Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2019-10-24 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 104 of the TNNT2 protein (p.Ala104Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs727504245, ExAC 0.01%). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 9140840, 28790153, 23396983, 27532257). However, in those individuals pathogenic alleles were also identified in different genes, which suggests that this c.311C>T variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 177633). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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; 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 Health, Inc RCV001171166 SCV001350178 uncertain significance Cardiomyopathy 2020-12-17 criteria provided, single submitter clinical testing This missense variant replaces alanine with valine at codon 104 of the TNNT2 protein. This variant is also known as c.341C>T, p.Ala114Val based on a different transcript NM_000364.4. Computational prediction suggests that this variant may have 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 several individuals affected with hypertrophic cardiomyopathy (PMID: 9140840, 23396983, 27532257, 28408708, 33297573, Lu et al. 2020 DOI: 10.13362/j.jpmed.202001002). 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 also been identified in 4/251490 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient 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 Left ventricular noncompaction 6 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.
Clinical Genetics,Academic Medical Center RCV001699043 SCV001917273 uncertain significance not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV001699043 SCV001953717 uncertain significance not provided no assertion criteria provided clinical testing

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