Submissions for variant NM_001276345.2(TNNT2):c.842A>T (p.Asn281Ile)

dbSNP: rs863225119

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000201488	SCV000256204	likely pathogenic	Hypertrophic cardiomyopathy 2		criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000762875	SCV000893255	likely pathogenic	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000762875	SCV001507073	likely pathogenic	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 271 of the TNNT2 protein (p.Asn271Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12707239, 20038417, 22857948, 23396983; Invitae). This variant is also known as c.833A>T (p.Asn278Ile). ClinVar contains an entry for this variant (Variation ID: 217495). 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 80%. Experimental studies have shown that this missense change affects TNNT2 function (PMID: 33025817). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx	RCV001589084	SCV001826487	uncertain significance	not provided	2019-12-18	criteria provided, single submitter	clinical testing	No data available from control populations to assess the frequency of this variant; however, this variant has not been detected at a significant frequency in presumably healthy individuals tested at GeneDx; Reported in ClinVar (ClinVar Variant ID# 217495; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33025817, 22857948, 12707239, 24093860)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798675	SCV002042857	likely pathogenic	Cardiomyopathy	2023-03-24	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV003225721	SCV003807440	likely pathogenic	Dilated cardiomyopathy 1D	2022-12-22	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PS4 moderated, PM2 moderated, PP1 supporting, BP4 supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330574	SCV004038751	uncertain significance	not specified	2023-08-21	criteria provided, single submitter	clinical testing	Variant summary: TNNT2 c.812A>T (p.Asn271Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 227734 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.812A>T (also known as N268I) has been reported in the literature in individuals affected with hypertrophic cardiomyopathy and sudden death (examples: Richard_2003, Brito_2012, Lopes_2013, Marsiglia_2013, Halvorsen_2021). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (example: Pettinato_2020). The following publications have been ascertained in the context of this evaluation (PMID: 22857948, 20038417, 34930847, 30297972, 23396983, 24093860, 33025817, 12707239). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV003362724	SCV004056458	uncertain significance	Cardiovascular phenotype	2023-07-18	criteria provided, single submitter	clinical testing	The p.N271I variant (also known as c.812A>T), located in coding exon 14 of the TNNT2 gene, results from an A to T substitution at nucleotide position 812. The asparagine at codon 271 is replaced by isoleucine, an amino acid with dissimilar properties. This variant has been detected in individuals with hypertrophic cardiomyopathy; however, in some cases, pathogenic variants in other cardiomyopathy-related genes were also detected, or gene analysis was limited to TNNT2 (Richard P et al. Circulation, 2003 May;107:2227-32; Gimeno JR et al. Rev Esp Cardiol, 2009 Dec;62:1473-7; Brito D et al. Rev Port Cardiol, 2012 Sep;31:577-87; Lopes LR et al. J Med Genet, 2013 Apr;50:228-39). A functional study has suggested that this variant may increase microtissue contraction; however, the physiological relevance of this finding is unclear (Pettinato AM et al. Circulation. 2020 Dec;142(23):2262-2275). This amino acid position is not well 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.
All of Us Research Program, National Institutes of Health	RCV001798675	SCV004816018	uncertain significance	Cardiomyopathy	2023-05-31	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with isoleucine at codon 271 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). Functional studies have shown that the variant may alter TNNT2 activity (PMID: 33025817). This variant has been reported in at least 4 individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 20038417, 22857948, 23396983). One of these individuals also carried a pathogenic variant in the MYH7 gene that could explain the observed phenotype (PMID: 23396983). This variant segregated with disease in multiple individuals in one family (PMID: 22857948). This variant has not been identified 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.