Total submissions: 9
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000225724 | SCV000209221 | likely pathogenic | not provided | 2023-01-25 | criteria provided, single submitter | clinical testing | Published in association with HCM, though patient-specific data were not provided (Pasquale et al., 2012; Cecconi et al., 2016; Walsh et al., 2017); 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; In vitro transcriptional assays showed transcriptional changes and altered contractility similar to other known pathogenic variants (Pettinato et al. 2020); This variant is associated with the following publications: (PMID: 22144547, 15631686, 27532257, 12746413, 27600940, 33025817) |
Invitae | RCV001300619 | SCV001489765 | uncertain significance | Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3 | 2023-03-22 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 83 of the TNNT2 protein (p.Glu83Lys). This variant is present in population databases (rs727504244, gnomAD 0.007%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TNNT2 function (PMID: 33025817). 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. ClinVar contains an entry for this variant (Variation ID: 177632). This variant is also known as c.277G>A p.Glu93Lys. This missense change has been observed in individual(s) with Brugada syndrome and/or hypertrophic cardiomyopathy (PMID: 22144547, 27532257, 27600940, 30847666, 32290750). |
CHEO Genetics Diagnostic Laboratory, |
RCV003149935 | SCV003838696 | uncertain significance | Cardiomyopathy | 2021-06-16 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV004019844 | SCV005036964 | uncertain significance | Cardiovascular phenotype | 2023-12-08 | criteria provided, single submitter | clinical testing | The p.E83K variant (also known as c.247G>A), located in coding exon 7 of the TNNT2 gene, results from a G to A substitution at nucleotide position 247. The glutamic acid at codon 83 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Mogensen J et al. J Med Genet, 2003 May;40:e59; Cecconi M et al. Int J Mol Med, 2016 Oct;38:1111-24; Walsh R et al. Genet Med, 2017 Feb;19:192-203; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Hughes RK et al. J Am Heart Assoc, 2021 Aug;10:e020227). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Laboratory for Molecular Medicine, |
RCV000154214 | SCV000203867 | uncertain significance | not specified | 2014-10-29 | no assertion criteria provided | clinical testing | proposed classification - variant undergoing re-assessment, contact laboratory |
Clinical Genetics, |
RCV000225724 | SCV001919548 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Genome Diagnostics Laboratory, |
RCV000225724 | SCV001929406 | likely pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000225724 | SCV001955149 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000225724 | SCV001972387 | likely pathogenic | not provided | no assertion criteria provided | clinical testing |