Submissions for variant NM_001276345.2(TNNT2):c.430C>G (p.Arg144Gly)

dbSNP: rs45525839

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036587	SCV000060242	likely pathogenic	Primary dilated cardiomyopathy	2014-02-21	criteria provided, single submitter	clinical testing	The Arg134Gly variant in TNNT2 has been reported in 1 individual with DCM, was a bsent from 506 control chromosomes, and segregated with disease in 4 affected re latives from 1 family (Hershberger 2008, Hershberger 2009). Data from large popu lation studies is insufficient to assess the frequency of this variant. This var iant has also been identified by our laboratory in 1 Caucasian individual with D CM (this family) and segregated with disease in 3 affected relatives, but was no t detected in 1 other affected relative (more distantly related). Arginine (Arg) at position 134 is conserved in evolution and the change to glycine (Gly) was p redicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, this variant is likely pathogenic, though a dditional studies are required to fully establish its clinical significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002513390	SCV003523947	pathogenic	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2022-04-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TNNT2 function (PMID: 20031601, 34161147). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 43639). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 20031601, 33025817). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 134 of the TNNT2 protein (p.Arg134Gly).
Genome-Nilou Lab	RCV003450702	SCV004181398	likely pathogenic	Dilated cardiomyopathy 1D	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003450703	SCV004181399	likely pathogenic	Cardiomyopathy, familial restrictive, 3	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003450701	SCV004181400	likely pathogenic	Hypertrophic cardiomyopathy 2	2023-04-11	criteria provided, single submitter	clinical testing