Submissions for variant NM_001276345.2(TNNT2):c.838G>A (p.Asp280Asn)

dbSNP: rs121964861

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851816	SCV002196538	uncertain significance	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2024-11-26	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 270 of the TNNT2 protein (p.Asp270Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 15542288). ClinVar contains an entry for this variant (Variation ID: 12417). 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%. Experimental studies have shown that this missense change affects TNNT2 function (PMID: 15542288, 15923195, 17932326). 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.
Ambry Genetics	RCV002415410	SCV002677635	uncertain significance	Cardiovascular phenotype	2021-06-03	criteria provided, single submitter	clinical testing	The p.D270N variant (also known as c.808G>A), located in coding exon 14 of the TNNT2 gene, results from a G to A substitution at nucleotide position 808. The aspartic acid at codon 270 is replaced by asparagine, an amino acid with highly similar properties. This variant has been detected in two affected individuals from a family with dilated cardiomyopathy (Mogensen J et al. J Am Coll Cardiol, 2004 Nov;44:2033-40). In vitro functional assays have indicated this variant may result in decreased calcium sensitivity of myofilaments, impaired protein-protein interactions, and/or reduced cooperativity of calcium binding; however, the precise physiological relevance of these findings is unclear (Mogensen J et al. J Am Coll Cardiol, 2004 Nov;44:2033-40; Mirza M et al. J Biol Chem, 2005 Aug;280:28498-506; Robinson P et al. Circ Res, 2007 Dec;101:1266-73). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Genome-Nilou Lab	RCV000013229	SCV004180510	uncertain significance	Dilated cardiomyopathy 1D	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003450633	SCV004180511	uncertain significance	Cardiomyopathy, familial restrictive, 3	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003450632	SCV004180512	uncertain significance	Hypertrophic cardiomyopathy 2	2023-04-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004802935	SCV005425669	uncertain significance	Cardiomyopathy	2024-08-06	criteria provided, single submitter	clinical testing
OMIM	RCV000013229	SCV000033476	pathogenic	Dilated cardiomyopathy 1D	2004-11-16	no assertion criteria provided	literature only