ClinVar Miner

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

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Athena Diagnostics Inc RCV000518398 SCV000614900 uncertain significance not specified 2017-06-05 criteria provided, single submitter clinical testing
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.
PreventionGenetics,PreventionGenetics RCV000119474 SCV000852337 likely pathogenic not provided 2013-11-19 criteria provided, single submitter clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000853260 SCV000996086 pathogenic Central core disease, autosomal recessive 2017-11-30 criteria provided, single submitter clinical testing This variant has previously been reported in the literature and by clinical laboratories in ClinVar as pathogenic or likely pathogenic (PMID: 16917943, 16835904) (ClinVar Variation ID 133046). There p.Arg44His variant has not been functionally characterized, but a different amino acid substitution at the same position (p.Arg44Cys) has functional evidence supporting the damaging effect on protein function (PMID: 23422674, 23459219, 12709367). RYR1 is missense intolerant, and in silico models predict the variant to be deleterious. The variant occurs at a highly conserved residue among vertebrates. It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0012% (3/242016) and thus is presumed to be rare. Based on the combined evidence, the variant is classified as pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000119474 SCV001151799 likely pathogenic not provided 2018-08-01 criteria provided, single submitter clinical testing
Leiden Muscular Dystrophy (RYR1) RCV000119474 SCV000154381 not provided not provided no assertion provided not provided
CSER _CC_NCGL, University of Washington RCV000148813 SCV000190552 uncertain significance Malignant hyperthermia, susceptibility to, 1 2014-06-01 no assertion criteria provided research

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