Submissions for variant NM_001276345.2(TNNT2):c.815A>G (p.Asn272Ser)

gnomAD frequency: 0.00001  dbSNP: rs397516483

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV002509186	SCV000060274	uncertain significance	not provided	2019-07-10	criteria provided, single submitter	clinical testing	The p.Asn262Ser variant in TNNT2 has been reported in at least 7 individuals with HCM and segregated with disease in 1 affected relative from 1 family (Ho 2009, Lopes 2015, Walsh 2016, LMM data). One of these individuals and their affected family member also carried an additional likely pathogenic variant in another HCM gene that could explain their disease (LMM data) and 1 individual carried a duplication of the TNNT2 gene (Lopes 2015). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 43671) and has been identified in 1/93044 European chromosomes by gnomAD (http://gnomad.broadinstitute.org/). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Asn262Ser variant is uncertain. ACMG/AMP Criteria applied: PM2, PS4_Moderate, BP4.
Color Diagnostics, LLC DBA Color Health	RCV000777960	SCV000914061	uncertain significance	Cardiomyopathy	2023-07-25	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 262 of the TNNT2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant does not significantly affect TNNT2 function (PMID: 33025817). This variant has been reported in over ten individuals affected with hypertrophic cardiomyopathy (PMID: 25524337, 26455666, 27552257, 32492895, 35514357). This variant has been identified in 1/215618 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae	RCV001071409	SCV001236713	uncertain significance	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 262 of the TNNT2 protein (p.Asn262Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 20031602, 25524337, 27532257). ClinVar contains an entry for this variant (Variation ID: 43671). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect TNNT2 function (PMID: 33025817). 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.
GeneDx	RCV002509186	SCV002818773	uncertain significance	not provided	2023-01-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20031602, 33025817, 32492895, 25524337, 27532257)
CeGaT Center for Human Genetics Tuebingen	RCV002509186	SCV004125322	uncertain significance	not provided	2023-06-01	criteria provided, single submitter	clinical testing	TNNT2: PM2, PS4:Supporting
Genome-Nilou Lab	RCV003450721	SCV004180523	uncertain significance	Dilated cardiomyopathy 1D	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003450722	SCV004180524	uncertain significance	Cardiomyopathy, familial restrictive, 3	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003450720	SCV004180525	uncertain significance	Hypertrophic cardiomyopathy 2	2023-04-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000777960	SCV004830406	uncertain significance	Cardiomyopathy	2023-09-17	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 262 of the TNNT2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant does not significantly affect TNNT2 function (PMID: 33025817). This variant has been reported in over ten individuals affected with hypertrophic cardiomyopathy (PMID: 25524337, 26455666, 27552257, 32492895, 35514357). This variant has been identified in 1/215618 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.