ClinVar Miner

Submissions for variant NM_002471.3(MYH6):c.1373T>C (p.Ile458Thr) (rs774807696)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000497477 SCV000590287 uncertain significance not provided 2017-06-05 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYH6 gene. The I458T variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is also not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The I458T 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 occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, I458T lacks observation in a significant number of affected individuals, segregation studies, and functional evidence, all of which would further clarify a role for this variant in disease.
Invitae RCV000647071 SCV000768858 uncertain significance Familial hypertrophic cardiomyopathy 14 2017-10-03 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 458 of the MYH6 protein (p.Ile458Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs774807696, ExAC 0.01%). This variant has not been reported in the literature in individuals with MYH6-related disease. ClinVar contains an entry for this variant (Variation ID: 432548). 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: "Possibly 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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