ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2149G>A (p.Asp717Asn) (rs1057524857)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000429496 SCV000536636 likely pathogenic not provided 2017-02-08 criteria provided, single submitter clinical testing The D717N variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D717N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (G716R, R719Q, R719QW, R719P) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity.
Invitae RCV000460699 SCV000546241 uncertain significance Hypertrophic cardiomyopathy 2017-09-05 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 717 of the MYH7 protein (p.Asp717Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MYH7-related disease. A computational algorithm designed to assess the pathogenicity of variants in MYH7 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). A different missense substitution at this codon (p.Asp717Gly) is reported to be deleterious (PMID: 25558701, 25935763). This indicates that the aspartic acid residue is important for MYH7 protein function. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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