ClinVar Miner

Submissions for variant NM_000364.4(TNNT2):c.565T>G (p.Ser189Ala) (rs377157235)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000541251 SCV000646904 uncertain significance Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2017-04-17 criteria provided, single submitter clinical testing This sequence change replaces serine with alanine at codon 179 of the TNNT2 protein (p.Ser179Ala). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and alanine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TNNT2-related disease. A different missense substitution at this codon ( p.Ser179Phe) has been determined to be pathogenic (PMID: 11034944,14722098, 27036851 ). This suggests that the serine residue is critical for TNNT2 protein function and that other missense substitutions at this position may also be pathogenic. 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, this is a novel variant that affects a residue that is required for TNNT2 function. However, the evidence available is currently insufficient to prove pathogenicity. For this reason, this variant has been classified as a Variant of Uncertain Significance.

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