ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.5395G>A (p.Glu1799Lys) (rs730880816)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158698 SCV000208633 likely pathogenic not provided 2012-12-04 criteria provided, single submitter clinical testing p.Glu1799Lys (GAA>AAA):c.5395 G>A in exon 37 of the MYH7 gene (NM_000257.2). The Glu1799Lys variant in the MYH7 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Glu1799Lys results in a non-conservative amino acid substitution of a negatively charged Glutamic Acid residue with a positively charged Lysine residue at a position that is conserved across species. In silico analysis predicts Glu1799Lys is probably damaging to the protein structure/function. Mutations in nearby residues (D1792G, Q1794E, E1801G, G1808A) have been reported in association with DCM, further supporting the functional importance of this region of the protein. Furthermore, the Glu1799Lys variant was not reported in the 1000 Genomes database (Kersey P et al., 2010), and the NHLBI ESP Exome Variant Server reports Glu1799Lys was not observed in approximately 6000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. In summary, Glu1799Lys is a good candidate for a disease-causing mutation. The variant is found in DCM panel(s).
Blueprint Genetics RCV000158698 SCV000927133 likely pathogenic not provided 2017-01-25 criteria provided, single submitter clinical testing
Invitae RCV000818295 SCV000958898 uncertain significance Hypertrophic cardiomyopathy 2018-08-22 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1799 of the MYH7 protein (p.Glu1799Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MYH7-related disease. ClinVar contains an entry for this variant (Variation ID: 181278). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; 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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