ClinVar Miner

Submissions for variant NM_000364.4(TNNT2):c.451C>T (p.Arg151Trp) (rs74315379)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000211866 SCV000203869 pathogenic Primary dilated cardiomyopathy; Hypertrophic cardiomyopathy 2015-05-12 criteria provided, single submitter clinical testing The p.Arg141Trp variant in TNNT2 has been reported in 3 individuals with DCM and segregated with disease in 16 affected relative from 2 families (Li 2001, Villa rd 2005) Additionally, the variant occurred de novo in 1 individual with LVNC (K laassan 2008). This variant has also been identified by our laboratory in 10 ind ividuals with cardiomyopathy, most of whom were diagnosed with DCM at very young ages (<10 years), segregated with disease in 1 affected relative, and occurred de novo in 1 individual. This variant was absent from large population studies. In vitro functional studies provide some evidence that the p.Arg141Trp variant m ay impact protein function (Lu 2003, Venkatraman 2003, Venkatraman 2005, Mirza 2 005, Robinson 2007, Liu 2012, Memo 2013, Sommerse 2013). In summary, this varian t meets our criteria to be classified as pathogenic for DCM in an autosomal domi nant manner (http://www.partners.org/personalizedmedicine/LMM) based upon segreg ation studies, absence from controls, and functional evidence.
GeneDx RCV000159296 SCV000209242 pathogenic not provided 2018-07-31 criteria provided, single submitter clinical testing The R141W pathogenic variant in the TNNT2 gene has been published multiple times in association with DCM (Li et al., 2001; Villard et al., 2005; Millat et al., 2011; Pugh et al., 2014; Long et al., 2015; Walsh et al., 2017). Li et al. (2001) first reported this variant to co-segregate with DCM in a large five-generation family, while Villard et al. (2005) similarly demonstrated co-segregation with DCM in another smaller family. Villard et al. (2005) also identified an apparently de novo case in which an individual with DCM harbored R141W. More recently, R141W was reported in an 11 year old male with DCM who underwent heart transplantation at 12 years old; exome testing confirmed R141W occurred de novo and also identified that this individual harbored compound heterozygous XIRP2 variants (Long et al., 2015). Furthermore, the R141W variant has been observed in three other probands referred for cardiomyopathy testing at GeneDx, and was apparently de novo in one of these probands, though identity testing was not performed.R141W results in a non-conservative amino acid substitution. Multiple published functional studies suggest that the R141W variant affects cardiac muscle contractile dynamics by decreasing Ca2+ sensitivity of activation, reducing affinity of Ca2+ binding in the troponin complex, and/or increasing the rate of Ca2+ dissociation from the thin filament (Lu et al., 2003; Mirza et al., 2005; Venkatraman et al., 2005; Robinson et al., 2007; Liu et al., 2012; Sommese et al., 2013; Memo et al., 2013; Gollapudi et al., 2015). Finally, R141W is not observed in large population cohorts (Lek et al., 2016).
Invitae RCV000524542 SCV000285650 pathogenic Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2018-10-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 141 of the TNNT2 protein (p.Arg141Trp). The arginine residue is highly 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 reported in individuals and families affected with dilated cardiomyopathy (DCM), segregating with the disease in two multigenerational families (PMID: 11684629, 15769782, 21846512, 24992688). In addition, this variant has been shown to occur de novo in an individual affected with DCM (PMID: 26656454). ClinVar contains an entry for this variant (Variation ID: 12414). Experimental studies have shown that this missense alters the myofibrillar Ca2+ sensitivity (PMID: 14654368, 23539503, 24367593). Furthermore, transgenic mice that express this variant exhibited dilated hearts and decreased systolic function (PMID: 18349139, 18606313). For these reasons, this variant has been classified as Pathogenic.
Center for Medical Genetics Ghent,University of Ghent RCV000013225 SCV000299243 pathogenic Left ventricular noncompaction 6 2016-01-01 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000159296 SCV000703511 pathogenic not provided 2016-12-12 criteria provided, single submitter clinical testing
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000710045 SCV000840422 pathogenic Familial isolated dilated cardiomyopathy 2018-04-20 criteria provided, single submitter clinical testing
OMIM RCV000013225 SCV000033472 pathogenic Left ventricular noncompaction 6 2001-10-30 no assertion criteria provided literature only
Blueprint Genetics RCV000157537 SCV000207283 pathogenic Primary dilated cardiomyopathy 2014-08-04 no assertion criteria provided clinical testing

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