ClinVar Miner

Submissions for variant NM_000364.4(TNNT2):c.287A>C (p.Asp96Ala) (rs397516455)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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identified by our laboratory in 2 Caucasian adults wi th HCM and segregated with disease in 1 affected relative (LMM unpublished data) .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 2018-03-21 criteria provided, single submitter clinical testing The D86A likely pathogenic variant in the TNNT2 gene has been reported numerous times in association with HCM (Van Driest et al., 2003; Predmore et al., 2010; Coppini et al., 2014; Murphy et al., 2016; Walsh et al., 2017). This variant has also been identified in several individuals referred for HCM genetic testing at GeneDx and is classified as likely pathogenic by another clinical laboratory in ClinVar (SCV000060226.4; Landrum et al., 2016). Furthermore, D86A is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D86A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution also occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Moreover, several missense variants in nearby residues (G82R, E83K, E83D, R84T, R84S, V85L, P87C, I90N, I90M) have been reported in the Human Gene Mutation Database in association with HCM or DCM (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, D86A in the TNNT2 gene is interpreted as a likely pathogenic variant.
Invitae RCV000556483 SCV000646894 likely pathogenic Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2018-11-28 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with alanine at codon 86 of the TNNT2 protein (p.Asp86Ala). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and alanine. This variant is present in population databases (rs397516455, ExAC 0.002%). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 12860912, 26914223, 27532257, 25031304, 20159828). ClinVar contains an entry for this variant (Variation ID: 43626). A computational algorithm designed to assess the pathogenicity of variants in TNNT2 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). 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.
Ambry Genetics RCV000618563 SCV000740173 uncertain significance Cardiovascular phenotype 2017-06-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence

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