ClinVar Miner

Submissions for variant NM_001276345.2(TNNT2):c.643C>T (p.Arg215Trp) (rs45586240)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159308 SCV000209254 pathogenic not provided 2017-12-15 criteria provided, single submitter clinical testing The R205W pathogenic variant in the TNNT2 gene has been reported in association with DCM (Hershberger et al., 2008; Hershberger et al., 2009; Rampersaud et al., 2011; Walsh et al., 2017). The R205W variant was identified in a 6 month old patient who was diagnosed with post-viral DCM and underwent heart transplantation at 12 years old (Hershberger et al., 2009; Rampersaud et al., 2011). Additionally, R205W was noted to segregate with disease in this family, although additional details were not provided (Rampersaud et al., 2011). R205W has also been identified both independently of and in conjunction with additional cardiogenetic variants in two other individuals referred for cardiomyopathy genetic testing at GeneDx; however, thus far, segregation data is limited or absent due to the lack of clinical information provided and/or insufficient participation by informative family members. The R205W variant is not observed in large population cohorts (Lek et al., 2016). The R205W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Furthermore, functional studies indicate R205W leads to decreased calcium sensitivity of force development in cardiac myocyte fibers (Hershberger et al., 2009). Other missense variants in the same residue (R205L and R205Q) have been reported in Human Gene Mutation Database in association with DCM (Stenson et al., 2014), further supporting the functional importance of this residue.
Ambry Genetics RCV000620262 SCV000737236 uncertain significance Cardiovascular phenotype 2017-02-16 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 two individuals with dilated cardiomyopathy (DCM) (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). 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, 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.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768716 SCV000900086 likely pathogenic Cardiomyopathy 2016-08-16 criteria provided, single submitter clinical testing
Invitae RCV000823611 SCV000964476 likely pathogenic Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2018-10-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 205 of the TNNT2 protein (p.Arg205Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with dilated cardiomyopathy or hypertrophic cardiomyopathy (PMID: 20031601, 23349452, 27532257). ClinVar contains an entry for this variant (Variation ID: 180554). Experimental studies have shown that this missense change decreases calcium sensitivity (PMID: 20031601). This variant disrupts the p.Arg205 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 15542288, 26498512), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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.
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

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