ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.1735G>A (p.Glu579Lys) (rs753907367)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000721425 SCV000617872 uncertain significance not provided 2017-10-26 criteria provided, single submitter clinical testing The E579K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The E579K variant is observed in 10/126,692 (0.01%) alleles from individuals of European background (Lek et al., 2016). This 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.
Invitae RCV000707225 SCV000836313 uncertain significance RYR1-Related Disorders 2018-09-12 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 579 of the RYR1 protein (p.Glu579Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs753907367, ExAC 0.007%). This variant has not been reported in the literature in individuals with RYR1-related disease. ClinVar contains an entry for this variant (Variation ID: 449573). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). This missense change is located in a region of the RYR1 protein where a significant number of previously reported RYR1 missense mutations are found (PMID: 16084090). These observations suggest that a previously unreported missense substitution within this region may affect protein function, but experiments have not been done to test this possibility. 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.
PreventionGenetics,PreventionGenetics RCV000721425 SCV000852489 uncertain significance not provided 2018-07-18 criteria provided, single submitter clinical testing

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