ClinVar Miner

Submissions for variant NM_001276345.2(TNNT2):c.421C>T (p.Arg141Trp)

dbSNP: rs74315380
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000030567 SCV000060239 likely pathogenic Primary dilated cardiomyopathy 2013-09-30 criteria provided, single submitter clinical testing The Arg131Trp variant in TNNT2 has been identified in 1 individual with LVNC whe re it was reported to have occurred de novo (Klaassen 2008) and has now been ide ntified by our laboratory in 2 individuals with DCM. It was not identified in la rge population studies. Additionally, studies have shown that the Arg131Trp vari ant alters calcium binding properties of the thin filaments (Robinson 2007, Lui 2012). However, these in vitro assays may not accurately represent biological fu nction. Arginine (Arg) at position 131 is highly conserved in mammals and across evolutionarily distant species and the change to tryptophan (Trp) was predicted to be pathogenic using a computational tool clinically validated by our laborat ory. This tool's pathogenic prediction is estimated to be correct 94% of the tim e (Jordan 2011). In summary, this variant is likely to be pathogenic, though add itional studies are required to fully establish its clinical significance.
GeneDx RCV000159291 SCV000209237 pathogenic not provided 2021-04-15 criteria provided, single submitter clinical testing Reported in ClinVar (ClinVar Variant ID# 12415; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); Published functional studies demonstrate a damaging effect as this variant alters troponin protein-protein interaction and calcium affinity (Mogensen et al., 2004; Mirza et al., 2005; Robinson et al., 2007; Liu et al., 2012; Gollapudi et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32458740, 17932326, 23302633, 24503780, 24817852, 28352236, 21551322, 24119082, 15923195, 22675533, 15542288, 20973921, 25163546, 18056765, 22337857, 27181684, 26183555, 25110706, 22464770, 27757084, 18506004, 27532257, 28611029, 31918855, 33025817, 32618513)
Invitae RCV000524541 SCV000541919 pathogenic Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3 2021-12-06 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 131 of the TNNT2 protein (p.Arg131Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dilated cardiomyopathy (DCM) and left ventricular non compaction (LVNC) (PMID: 15542288, 18506004, 21551322, 24119082). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12415). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TNNT2 function (PMID: 15542288, 15923195, 17932326, 22675533). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588329 SCV000697562 likely pathogenic Cardiovascular phenotype 2017-06-22 criteria provided, single submitter clinical testing Variant summary: The TNNT2 c.391C>T (p.Arg131Trp) variant results in a non-conservative amino acid substitution located in the tropomyosin binding domain of the protein (Mogensen_2004, Klaassen_2008). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/116588 control chromosomes at a frequency of 0.0000086, which does not exceed the estimated maximal expected allele frequency of a pathogenic TNNT2 variant (0.000175). This variant has been found in 4 probands (1st with DCM, 2nd with LVNC, 3rd with DCM/LVNC, and 4th with DCM) in the reported literature. In the first family, it was found to co-segregate with DCM in at least two affected members. In second family, the variant was found to be de novo in the affected proband; however, it is not specified whether paternity was confirmed. In the third family, affected mother was available for genotyping but she did not carry the variant. From the results of third family, authors assume the variant either to be VUS or disease-causing having reduced penetrance. The unaffected father in the family was not available for genotyping. Though this lack of co-segregation may indicate that it may not be pathogenic, the possibility that another familial variant was explaining the phenotype in the mother which remained untransmitted in the proband cannot be ruled out. In addition, this variant could have a reduced penetrance and could have been transmitted from the unaffected father, or it could have originated de novo. The variant has also been reported in two patients with DCM by LMM/PH (unpublished findings). Several independent functional studies dating from 2004 to 2016 have demonstrated that this variant results in a depressed myofilament calcium sensitivity in alpha-MHC (myosin heavy chains) thereby inducing a more severe DCM-like contractile phenotype against an alpha-MHC background. These results are consistent with an established molecular mechanism of disease due to an alteration in the contractile dynamics in the presence of mutations in TNNT2. Three diagnostic centers via ClinVar interpret the variant as pathogenic/likely pathogenic, without evidence for independent evaluation. There are also other potentially pathogenic missense variants around this variant (such as such as p.E128K, p.R130C and p.R134G), suggesting a notion that the region may have a functional importance. Taken all evidences together, this variant is classified as Likely Pathogenic until additional reports demonstrating unequivocal co-segregation with disease in independent families with multiple affected and unaffected members are obtained.
Ambry Genetics RCV000588329 SCV000736576 likely pathogenic Cardiovascular phenotype 2016-04-26 criteria provided, single submitter clinical testing The p.R131W variant (also known as c.391C>T), located in coding exon 9 of the TNNT2 gene, results from a C to T substitution at nucleotide position 391. The arginine at codon 131 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been previously reported in individuals with dilated cardiomyopathy (DCM) and left ventricular non-compaction (LVNC), and was reported as occurring de novo in a proband with LVNC and LV dilation (Mogensen J et al. J Am Coll Cardiol. 2004;44(10):2033-40; Klaassen S et al. Circulation. 2008;117(22):2893-901 (reported as c.450C>T); Pugh TJ et al. Genet Med. 2014;16(8):601-8). One study identified this variant in a family with a DCM/LVNC complex phenotype, where it was reportedly absent in the proband's affected parent, though clinical details were limited (Merlo M et al. Clin Transl Sci. 2013;6(6):424-8). Functional studies suggest this variant to result in impaired protein interaction and altered calcium binding properties (Mogensen et al. 2004; Mirza M et al. J Biol Chem. 2005; 280(31):28498-506; Robinson P et al. Circ Res. 2007;101(12):1266-73). This variant was previously reported in the SNPDatabase as rs74315380. Based on data from ExAC, the T allele has an overall frequency of approximately <0.01% (1/101255). This variant was not reported in population-based cohorts in the following databases: NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
OMIM RCV000013226 SCV000033473 pathogenic Dilated cardiomyopathy 1D 2008-06-03 no assertion criteria provided literature only

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