Submissions for variant NM_001276345.2(TNNT2):c.643C>T (p.Arg215Trp)

dbSNP: rs45586240

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159308	SCV000209254	pathogenic	not provided	2022-12-29	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31983221, 30847666, 15542288, 22337857, 21483645, 23349452, 20031601, 27532257, 25649125, 27576561, 19412328, n/a, 28352236, 23897817)
Ambry Genetics	RCV000620262	SCV000737236	uncertain significance	Cardiovascular phenotype	2024-02-07	criteria provided, single submitter	clinical testing	The p.R205W variant (also known as c.613C>T), located in coding exon 12 of the TNNT2 gene, results from a C to T substitution at nucleotide position 613. The arginine at codon 205 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in dilated cardiomyopathy (DCM) cohorts; however, clinical details were limited in some cases (Hershberger RE et al. Clin Transl Sci, 2008 May;1:21-6; Hershberger RE et al. Circ Cardiovasc Genet, 2009 Aug;2:306-13; van Spaendonck-Zwarts KY et al. Eur. J. Heart Fail., 2013 Jun;15:628-36; Walsh R et al. Genet Med, 2017 02;19:192-203; Akinrinade O et al. Eur Heart J, 2015 Sep;36:2327-37). Functional studies suggest this alteration has an impact on calcium sensitivity (Hershberger RE et al. Circ Cardiovasc Genet, 2009 Aug;2:306-13). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768716	SCV000900086	likely pathogenic	Cardiomyopathy	2019-09-16	criteria provided, single submitter	clinical testing
Invitae	RCV000823611	SCV000964476	pathogenic	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 205 of the TNNT2 protein (p.Arg205Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dilated cardiomyopathy or hypertrophic cardiomyopathy (PMID: 20031601, 23349452, 26084686, 26779504, 27532257, 30847666, 31983221). This variant is also known as c.634C>T (p.R212W). ClinVar contains an entry for this variant (Variation ID: 180554). 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 have shown that this missense change affects TNNT2 function (PMID: 20031601, 27411801). This variant disrupts the p.Arg205 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26498512; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193335	SCV001362087	likely pathogenic	Primary familial dilated cardiomyopathy	2019-01-21	criteria provided, single submitter	clinical testing	Variant summary: TNNT2 c.613C>T (p.Arg205Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 246252 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.613C>T has been reported in the literature in individuals affected with Dilated Cardiomyopathy (Hershberger 2008, Hershberger 2009, Rampersaud 2011, Walsh 2017, Akinrinade 2015, Ware 2018, van Spaendonck-Zwarts 2013), and in one patient with severe Hypertrophic Cardiomyopathy (HCM), however in this case the patient also carried another causative variant pathogenic for HCM (MYL2 c.173G>A (p.R58Q)) (Jaafar 2015). These data indicate that the variant is likely to be associated with disease. Two functional studies reported the variant to reduce calcium sensitivity (Hershberger 2009, Michael 2016), that is consistent with the cellular pathomechanism observed for other variants associated with DCM (see e.g. in England 2017). In addition, a different variant at the same codon has been reported in association with DCM (p.Arg205Leu), indicating the functional significance of this amino acid. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Blueprint Genetics	RCV000157539	SCV000207285	likely pathogenic	Primary dilated cardiomyopathy	2014-04-29	no assertion criteria provided	clinical testing