ClinVar Miner

Submissions for variant NM_000364.4(TNNT2):c.254T>G (p.Val85Gly) (rs730881095)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159270 SCV000209216 uncertain significance not provided 2019-01-11 criteria provided, single submitter clinical testing The V75G variant of uncertain significance in the TNNT2 gene has not been published as pathogenic or been reported as benign to our knowledge. The V75G 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). In silico analysis predicts this variant is probably damaging to the protein structure/function. This substitution occurs at a position where only amino acids with similar properties to valine are tolerated across species. However, the V75G variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties.
Invitae RCV000460783 SCV000541913 uncertain significance Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2018-08-22 criteria provided, single submitter clinical testing This sequence change replaces valine with glycine at codon 75 of the TNNT2 protein (p.Val75Gly). The valine residue is moderately conserved and there is a moderate physicochemical difference between valine and glycine. This variant is present in population databases (rs730881095, ExAC 0.02%) but has not been reported in the literature in individuals with a TNNT2-related disease. ClinVar contains an entry for this variant (Variation ID: 181609). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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