ClinVar Miner

Submissions for variant NM_000364.4(TNNT2):c.856G>A (p.Gly286Arg) (rs757664792)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489362 SCV000576672 uncertain significance not provided 2017-04-21 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the TNNT2 gene. The G279R variant has not been published as pathogenic or been reported as benign to our knowledge. This variant 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 G279R 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. Additionally, this substitution occurs at a position that is conserved across species. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, the G279R variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity.
Invitae RCV000646063 SCV000767820 uncertain significance Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2017-09-07 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 279 of the TNNT2 protein (p.Gly279Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs757664792, ExAC 0.002%). This variant has not been reported in the literature in individuals with TNNT2-related disease. ClinVar contains an entry for this variant (Variation ID: 426271). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

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