ClinVar Miner

Submissions for variant NM_000364.4(TNNT2):c.418C>T (p.Arg140Cys) (rs397516463)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036583 SCV000060238 pathogenic Hypertrophic cardiomyopathy 2019-02-01 criteria provided, single submitter clinical testing The p.Arg130Cys variant in TNNT2 (ClinVar variation ID: 43636) has been reported in at least 8 families with hypertrophic cardiomyopathy (HCM) and segregated wi th disease in at least 8 individuals across these families (Fujita 2013, Koga 19 96, Olivotto 2008, Song 2005, Torricelli 2003, Zou 2013). This variant was absen t from large population studies. In vitro functional studies provide some eviden ce that the p.Arg130Cys variant may impact protein function (Harada 2004, Gangad haran 2017). However, these types of assays may not accurately represent biologi cal function. Computational prediction tools and conservation analysis suggest t hat the p.Arg130Cys variant may impact the protein, though this information is n ot predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon segregation studies, absence from controls, and functional evidence. ACMG/AMP criteria applied: PP1_Strong, PM2, PS4_Moderate, PP3, PS3_Supporting.
GeneDx RCV000159290 SCV000209236 pathogenic not provided 2018-06-14 criteria provided, single submitter clinical testing The R130C pathogenic variant in the TNNT2 gene has been reported in multiple unrelated individuals with HCM (Torricelli et al., 2003; Song et al., 2005). Fujita et al. (2013) identified the R130C variant in two members of a Japanese family with HCM who also harbored the F110I variant in TNNT2. Additionally, the R130C variant has been classified as a likely pathogenic variant by other clinical laboratories in ClinVar (SCV000060238.4, SCV000320661.1, SCV000280524.1; Landrum et al., 2016). The R130C variant is not observed in large population cohorts (Lek et al., 2016; Exome Variant Server). Furthermore, functional studies of the R130C variant found that this variant alters the contractile properties of cardiac fibers (Harada & Potter, 2004). The R130 residue is located in a region essential for tropomyosin binding; therefore R130C is expected to reduce the troponin T binding affinity for tropomyosin (Harada & Potter, 2004). R130C results in a non-conservative amino acid substitution at a position that is conserved across species. Missense variants in nearby residues (K124N, R126W, E128K, R131W, R134G, Q138H) have been reported in association with cardiomyopathy (Stenson et al., 2014).
Ambry Genetics RCV000243733 SCV000320661 likely pathogenic Cardiovascular phenotype 2015-11-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Other data supporting pathogenic classification
Invitae RCV000468121 SCV000541920 pathogenic Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 130 of the TNNT2 protein (p.Arg130Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (rs397516463, ExAC no frequency). This variant has been reported in many individuals and families affected with hypertrophic cardiomyopathy (PMID: 14636924, 15563892, 17456375, 23283745, 23494605, 25524337). This variant is also known as p.Arg140Cys in the literature. ClinVar contains an entry for this variant (Variation ID: 43636). A computational algorithm designed to assess the pathogenicity of variants in TNNT2 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). For these reasons, this variant has been classified as Pathogenic.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000159290 SCV000280524 likely pathogenic not provided 2015-05-01 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. TNNT2 variant Arg130Cys (R130C; C>T at the nucleotide level) This variant has been reported in at least 5 unrelated cases of HCM, with segregation data for at least 3 families. Koga et al. (1996) first detected it in 3 different Japanese families. The variant was “present in all affected family members” (a total of 6 people), but specific segregation data is not provided. Toricelli et al. (2003) reported Arg130Cys in an HCM patient from Tuscany with only weak segregation data: The variant was found in the proband and his affected sister. Olivotto et al. (2008) appear to be referring to that same proband. Song et al. (2005) found the variant in one Chinese family with a history of SCD, where it segregated with disease in 4 affected family members—although their degree of relationship is not reported. (Also supposedly mentioned in an abstract by Nakata et al. in 1996.) Variation at nearby loci of TNNT2 (within 10 amino acids to either side) has been associated with disease, supporting the functional importance of this region of the protein. This includes Lys124Asn (Willott et al. 2010; Harvard Sarcomere Protein Gene Mutation Database), Arg131Trp (in DCM/LVNC; Mogensen et al. 2004), Arg131Gly (in DCM; Willott et al. 2010), Arg134Gly (in DCM; Hershberger et al. 2009; Willott et al. 2010), and Arg139His (Morales et al. 2010). This is a nonconservative amino acid change from a basic, positively-charged Arginine to a polar, neutral Cysteine (capable of forming disulfide bridges). The Arginine at codon 130 is completely conserved across 32 vertebrate species examined. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “probably damaging”. In vitro data from Harada & Potter (2004) shows the variant to alter the contractile properties of skinned cardiac fibers. In total the variant has not been seen in ~5670 published controls and publicly available population datasets. There is no variation at codon 130 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~3500 Caucasian and ~1800 African American individuals (as of 1/15/2012). There is no variation at this codon listed in dbSNP or 1000 genomes (as of 1/15/2012). The variant was not observed in published controls: Koga et al. (1996) did not detect Arg130Cys in more than 100 Japanese controls. Toricelli et al. (2003) did not find it in 150 healthy controls from Tuscany. Song et al. (2005) did not find it in 120 Chinese controls.

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