ClinVar Miner

Submissions for variant NM_001276345.2(TNNT2):c.451C>T (p.Arg151Trp)

dbSNP: rs74315379
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 17
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham 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 2023-01-23 criteria provided, single submitter clinical testing 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); 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: 24367593, 28166811, 24992688, 25611685, 33336002, 34935411, 25681424, 23539503, 17932326, 12923187, 15623536, 11684629, 15923195, 22675533, 21846512, 15769782, 27936050, 27532257, 24503780, 21310275, 26656454, no PMID, 33025817, 34540771, 33906374, 32746448, 32758068, 34076677, 35288587, 14654368, 18606313)
Invitae RCV000524542 SCV000285650 pathogenic Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3 2023-08-17 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 141 of the TNNT2 protein (p.Arg141Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dilated cardiomyopathy (DCM), segregating with the disease in two multigenerational families (PMID: 11684629, 15769782, 21846512, 24992688, 26656454). 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: 12414). 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. Experimental studies have shown that this missense change affects TNNT2 function (PMID: 14654368, 18349139, 18606313, 23539503, 24367593). For these reasons, this variant has been classified as Pathogenic.
Center for Medical Genetics Ghent, University of Ghent RCV000013225 SCV000299243 pathogenic Dilated cardiomyopathy 1D 2016-01-01 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001375512 SCV001572362 pathogenic Cardiomyopathy 2021-04-15 criteria provided, single submitter clinical testing Variant summary: TNNT2 c.421C>T (p.Arg141Trp) 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 was absent in 250316 control chromosomes. c.421C>T has been reported in the literature in multiple individuals affected with Cardiomyopathy (e.g. Li_2001, Millart_2011, Alfares_2015, Long_2015, Walsh_2016). These data indicate that the variant is very likely to be associated with disease. In a large multi-generational family study, the variant was detected in at least 14 affected family members, although several unaffected individuals also carried the variant, suggesting incomplete penetrance (e.g. Li_2001). The variant has also been reported as a de-novo mutation in an individual with sporadic disease (e.g. Long_2015). Multiple publications report in-vitro or in-vivo experimental evidence that the variant results in calcium desensitization in cardiac muscle fibers (e.g. Lu_2003, Mirza_2005, Gollapudi_2015). Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV003225021 SCV003921976 pathogenic TNNT2 -related cardiomyopathies 2021-03-23 criteria provided, single submitter clinical testing 0103 - Dominant negative and gain of function are reported mechanisms of disease in this gene and is associated with TNNT2-related cardiomyopathies (PMID: 18612386). 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (2 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated troponin domain (NCBI, PDB). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported as pathogenic in multiple patients with TNNT2-related cardiomyopathies, and is often annotated as p.(R141W) using an alternative transcript. It has been reported as de novo in some individuals, and has also been observed to segregate with the disease in families (ClinVar, PMID: 26656454). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine RCV000013225 SCV004048125 pathogenic Dilated cardiomyopathy 1D criteria provided, single submitter clinical testing The missense variant c.451C>T (p.Arg151Trp) in TNNT2 gene has been reported in individuals and families affected with dilated cardiomyopathy (Li D et.al.,2001). This variant has been reported to the ClinVar database as Pathogenic .The p.Arg151Trp variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Arg at position 151 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Arg151Trp in TNNT2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic .
Genome-Nilou Lab RCV000013225 SCV004181375 pathogenic Dilated cardiomyopathy 1D 2023-04-11 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV003450629 SCV004181376 pathogenic Cardiomyopathy, familial restrictive, 3 2023-04-11 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV003450628 SCV004181377 pathogenic Hypertrophic cardiomyopathy 2 2023-04-11 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001375512 SCV004239777 pathogenic Cardiomyopathy 2023-06-23 criteria provided, single submitter clinical testing
OMIM RCV000013225 SCV000033472 pathogenic Dilated cardiomyopathy 1D 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
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000159296 SCV001741499 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000159296 SCV001973668 pathogenic not provided no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.