ClinVar Miner

Submissions for variant NM_002471.3(MYH6):c.5519A>G (p.Lys1840Arg) (rs373629059)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000254495 SCV000319976 uncertain significance Cardiovascular phenotype 2015-07-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient or conflicting evidence
Invitae RCV000477541 SCV000546143 uncertain significance Familial hypertrophic cardiomyopathy 14 2017-04-26 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 1840 of the MYH6 protein (p.Lys1840Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs373629059, ExAC 0.01%). This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 27483260). ClinVar contains an entry for this variant (Variation ID: 264214). 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 variant is a rare missense change with uncertain impact on protein function. It is not expected to cause disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000521903 SCV000618330 uncertain significance not provided 2017-09-19 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYH6 gene. The K1840R variant has been reported previously as a variant of uncertain significance in an individual with late-onset HCM (Rubattu et al., 2016). The K1840R variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is likely damaging to the protein structure/function. However, the K1840R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, no missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014).

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