Submissions for variant NM_001276345.2(TNNT2):c.677G>A (p.Arg226Lys)

gnomAD frequency: 0.00001  dbSNP: rs1205564576

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000618092	SCV000736316	uncertain significance	Cardiovascular phenotype	2022-07-26	criteria provided, single submitter	clinical testing	The p.R216K variant (also known as c.647G>A), located in coding exon 12 of the TNNT2 gene, results from a G to A substitution at nucleotide position 647. The arginine at codon 216 is replaced by lysine, an amino acid with highly similar properties. This alteration was reported in a sudden unexplained death cohort (Lin Y et al. Circ Cardiovasc Genet, 2017 Dec;10:). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000703105	SCV000831987	uncertain significance	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2025-02-03	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 216 of the TNNT2 protein (p.Arg216Lys). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with sudden unexplained death (PMID: 29247119). ClinVar contains an entry for this variant (Variation ID: 518816). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt TNNT2 protein function with a negative predictive value of 80%. 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.
Color Diagnostics, LLC DBA Color Health	RCV001189934	SCV001357330	uncertain significance	Cardiomyopathy	2019-12-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with lysine at codon 216 of the TNNT2 protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/31404 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV000703105	SCV002793420	uncertain significance	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2023-12-29	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003451470	SCV004181257	uncertain significance	Dilated cardiomyopathy 1D	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003451471	SCV004181258	uncertain significance	Cardiomyopathy, familial restrictive, 3	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003451469	SCV004181259	uncertain significance	Hypertrophic cardiomyopathy 2	2023-04-11	criteria provided, single submitter	clinical testing