Submissions for variant NM_001276345.2(TNNT2):c.277G>A (p.Glu93Lys)

gnomAD frequency: 0.00001  dbSNP: rs727504244

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	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, Children's Hospital of Eastern Ontario	RCV003149935	SCV003838696	uncertain significance	Cardiomyopathy	2021-06-16	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized 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, Academic Medical Center	RCV000225724	SCV001919548	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000225724	SCV001929406	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000225724	SCV001955149	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000225724	SCV001972387	likely pathogenic	not provided		no assertion criteria provided	clinical testing