ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.4838G>A (p.Arg1613Lys) (rs397516230)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000767039 SCV000620438 uncertain significance not provided 2017-09-18 criteria provided, single submitter clinical testing The c.4838 G>A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.4838 G>A variant is not observed in large population cohorts (Lek et al., 2016). Multiple in-silico splice prediction models predict that c.4838 G>A creates a cryptic splice donor site which may supplant the natural donor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies the actual effect of c.4838 G>A on splicing in this individual is unknown. If c.4838 G>A does not alter splicing, it will result in the R1613K missense change. The R1613K variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and missense variants in nearby residues (R1608P, E1610Q, L1612P) have been reported in the Human Gene Mutation Database in association with MYH7-related disorders (Stenson et al., 2014). In silico analysis predicts this variant is probably damaging to the protein structure/function.
Invitae RCV000456855 SCV000546235 uncertain significance Hypertrophic cardiomyopathy 2018-04-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 1613 of the MYH7 protein (p.Arg1613Lys). The arginine residue is highly conserved and there is a small physicochemical difference between arginine 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. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035935 SCV000059586 uncertain significance not specified 2013-08-22 criteria provided, single submitter clinical testing The Arg1613Lys variant in MYH7 has been identified by our laboratory in 1 Caucas ian individual with DCM, and was not identified in large population studies. Com putational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. Additional information is needed to fully assess the clinical signi ficance of the Arg1613Lys variant.

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