Submissions for variant NM_001276345.2(TNNT2):c.287A>C (p.Asp96Ala)

gnomAD frequency: 0.00001  dbSNP: rs397516455

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036571	SCV000060226	likely pathogenic	Hypertrophic cardiomyopathy	2014-11-14	criteria provided, single submitter	clinical testing	The p.Asp86Ala variant in TNNT2 has been previously reported in 1 adult with HCM (Van Driest 2003) and was identified by our laboratory in 2 Caucasian adults wi th HCM and segregated with disease in 1 affected relative (LMM unpublished data) . Data from large population studies is insufficient to assess the frequency of this variant. Aspartic acid (Asp) at position 86 is highly conserved in mammals and across evolutionarily distant species and the change to alanine (Ala) was pr edicted 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, although additional studies are required to fully establish its clinical significance, the p.Asp86Ala variant is likely path ogenic.
GeneDx	RCV000505760	SCV000209224	likely pathogenic	not provided	2023-03-01	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15631686, 26914223, 28973951, 25031304, 25524337, 15201162, 12860912, 20159828, 27532257, 29121657, 21310275, 27535533, 34699384, 35514357)
Invitae	RCV000556483	SCV000646894	pathogenic	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 86 of the TNNT2 protein (p.Asp86Ala). This variant is present in population databases (rs397516455, gnomAD 0.0009%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12860912, 20159828, 25031304, 26914223, 27532257). ClinVar contains an entry for this variant (Variation ID: 43626). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on TNNT2 function (PMID: 28973951). This variant disrupts the p.Asp86 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been observed in individuals with TNNT2-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000618563	SCV000740173	likely pathogenic	Cardiovascular phenotype	2024-02-06	criteria provided, single submitter	clinical testing	The p.D86A variant (also known as c.257A>C), located in coding exon 7 of the TNNT2 gene, results from an A to C substitution at nucleotide position 257. The aspartic acid at codon 86 is replaced by alanine, an amino acid with dissimilar properties. This alteration has been detected in multiple individuals with hypertrophic cardiomyopathy and has been reported to segregate with disease in several small families (Van Driest SL et al. Circulation, 2003 Jul;108:445-51; Coppini R et al. J. Am. Coll. Cardiol., 2014 Dec;64:2589-2600; Viswanathan SK et al. PLoS ONE, 2017 Nov;12:e0187948; Walsh R et al. Genet. Med., 2017 Feb;19:192-203; Ambry internal data; external communication). Internal structural analysis indicates that this variant may impact the protein-protein interaction with tropomyosin (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000556483	SCV002791893	likely pathogenic	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2021-09-16	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003450679	SCV004181504	likely pathogenic	Dilated cardiomyopathy 1D	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003450680	SCV004181505	likely pathogenic	Cardiomyopathy, familial restrictive, 3	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003450678	SCV004181507	likely pathogenic	Hypertrophic cardiomyopathy 2	2023-04-11	criteria provided, single submitter	clinical testing