ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.131G>A (p.Arg44His) (rs139161723)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000518398 SCV000614900 uncertain significance not specified 2017-06-05 criteria provided, single submitter clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000148813 SCV000190552 uncertain significance Malignant hyperthermia, susceptibility to, 1 2014-06-01 no assertion criteria provided research
GeneDx RCV000119474 SCV000491287 likely pathogenic not provided 2016-06-03 criteria provided, single submitter clinical testing A R44H variant has been reported previously in association with malignant hyperthermia; however, additional clinical information was not provided and functional characterization of the variant was not completed (Galli et al., 2006; Robinson et al., 2006). The R44H variant was not observed with any significant frequency in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R44H 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 in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, missense variants at the same position (R44C) and in nearby residues (G40V, F41S) have been reported in the Human Gene Mutation Database in association with RYR1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV000531069 SCV000659808 likely pathogenic RYR1-Related Disorders 2016-09-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 44 of the RYR1 protein (p.Arg44His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs139161723, ExAC 0.002%). This variant has been reported in the literature in individuals with malignant hyperthermia (PMID:  16835904, 16917943). ClinVar contains an entry for this variant (Variation ID: 133046). 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: "Probably Damaging"; Align-GVGD: "Class C0"). This missense change is located in the N-terminal mutational hotspot of the RYR1 protein where a significant number of missense mutations previously reported to be pathogenic are found (PMID: 16084090). A different missense substitution at this codon (p.Arg44Cys) has been determined to be pathogenic (PMID: 12709367, 23459219, 23919265). This suggests that the arginine residue is critical for RYR1 protein function and that other missense substitutions at this position may also be pathogenic. In summary, this variant is a rare missense change that occurs at the same codon as a known pathogenic variant. In addition, it has been previously reported in individuals affected with RYR1-related disease. For these reasons, this variant has been classified as Likely Pathogenic.
Leiden Muscular Dystrophy (RYR1) RCV000119474 SCV000154381 not provided not provided no assertion provided not provided
PreventionGenetics RCV000119474 SCV000852337 likely pathogenic not provided 2013-11-19 criteria provided, single submitter clinical testing

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