ClinVar Miner

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

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel,ClinGen RCV000148813 SCV001816147 uncertain significance Malignant hyperthermia, susceptibility to, 1 2021-03-18 reviewed by expert panel curation This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of arginine with histidine at codon 44 of the RYR1 protein, p.(Arg44His). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.000066, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:30236257 ). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1, (PMID: 21118704). A REVEL score >0.85 supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1, PP3_Moderate.
GeneDx RCV000119474 SCV000491287 likely pathogenic not provided 2021-04-14 criteria provided, single submitter clinical testing Reported in association with malignant hyperthermia (Robinson et al., 2006; Galli et al., 2006); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 20301325, 16917943, 25637381, 16835904)
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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