ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.625G>A (p.Glu209Lys) (rs771058055)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000542622 SCV000659983 uncertain significance RYR1-Related Disorders 2018-04-02 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 209 of the RYR1 protein (p.Glu209Lys). 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 (rs771058055, ExAC 0.01%). This variant has been observed in a family affected with malignant hyperthermia (PMID: 21455645). However, in this family, a pathogenic variant was also identified on the same allele in RYR1 (p.Arg2336His) which suggests that this c.625G>A variant was not the primary cause of 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"). 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, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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