Total submissions: 17
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular 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. |
Gene |
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, |
RCV000013225 | SCV000299243 | pathogenic | Dilated cardiomyopathy 1D | 2016-01-01 | criteria provided, single submitter | clinical testing | |
Eurofins Ntd Llc |
RCV000159296 | SCV000703511 | pathogenic | not provided | 2016-12-12 | criteria provided, single submitter | clinical testing | |
Center of Genomic medicine, |
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, |
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, |
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, |
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- |
RCV000013225 | SCV004181375 | pathogenic | Dilated cardiomyopathy 1D | 2023-04-11 | criteria provided, single submitter | clinical testing | |
Genome- |
RCV003450629 | SCV004181376 | pathogenic | Cardiomyopathy, familial restrictive, 3 | 2023-04-11 | criteria provided, single submitter | clinical testing | |
Genome- |
RCV003450628 | SCV004181377 | pathogenic | Hypertrophic cardiomyopathy 2 | 2023-04-11 | criteria provided, single submitter | clinical testing | |
CHEO Genetics Diagnostic Laboratory, |
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, |
RCV000159296 | SCV001741499 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000159296 | SCV001973668 | pathogenic | not provided | no assertion criteria provided | clinical testing |