ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.742G>C (p.Gly248Arg) (rs1801086)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000119714 SCV000329914 pathogenic not provided 2016-08-30 criteria provided, single submitter clinical testing The G248R pathogenic variant in the RYR1 gene has been reported previously in the heterzygous state in associationwith malignant hyperthermia (Gillies et al., 2008). The G248R variant was not observed in approximately 6500individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is nota common benign variant in these populations. The G248R variant is a conservative amino acid substitution, whichis not likely to impact secondary protein structure as these residues share similar properties. This substitution occursat a position where amino acids with similar properties to Glycine are tolerated across species. In silico analysispredicts this variant is probably damaging to the protein structure/function. A different nucleotide substitution (c.724G>A) resulting in the same amino acid change (G248R) been reported in the Human Gene Mutation Database inassociation with malignant hyperthermia (Stenson et al., 2014), supporting the functional importance of the G248residue. Additionally, functional studies of the c.742G>A variant (Tong et al., 1991; Tong et al., 1999) and a proteincrystal structure study (Kimlicka et al., 2013) all support that the G248 residue is critical for normal RYR1 function.Therefore, we interpret G248R as a known pathogenic variant.
Invitae RCV000704587 SCV000833540 pathogenic RYR1-Related Disorders 2018-02-06 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 248 of the RYR1 protein (p.Gly248Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs1801086, ExAC 0.006%). This variant has been reported in numerous individuals affected with malignant hyperthermia susceptibility (PMID: 1354642, 18564801, 15448513, 11575529, 23558838, 19648156). ClinVar contains an entry for this variant (Variation ID: 133203). 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: 6917943, 12565913, 23919265). These observations suggest that a previously unreported missense substitution within this region may affect protein function, and experimental studies have shown that this missense change results in a hyperactive RYR1 channel (PMID: 9334205, 9873004, 27857962). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics,PreventionGenetics RCV000119714 SCV000852774 pathogenic not provided 2013-11-19 criteria provided, single submitter clinical testing
Leiden Muscular Dystrophy (RYR1) RCV000119714 SCV000154621 not provided not provided no assertion provided not provided

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