ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.3418C>T (p.Arg1140Cys)

gnomAD frequency: 0.00001  dbSNP: rs193922776
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Total submissions: 5
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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 RCV001580435 SCV001810124 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-04-06 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 cysteine at codon 1140 of the RYR1 protein, p.Arg1140Cys. The maximum allele frequency for this variant among the six major gnomAD populations is AMR: 0.00012, 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), (PMID:30236257). However, the high MAF in the AMR population in gnomAD precludes the use of PS4. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.807 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. No criteria implemented.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000456108 SCV000540256 uncertain significance not specified 2016-12-21 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in 1 paper in HGMD in an unspecified number of malignant hyperthermia patients (classified as DM). This variant is present in ClinVar with no interpretation. The variant has a Max MAF of 0.006% in ExAC (1 allele) and 0.01% in gnomAD (4 alleles). Variant is not present in emhg.org database.
Fulgent Genetics, Fulgent Genetics RCV002483207 SCV002789537 uncertain significance Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome 2021-08-27 criteria provided, single submitter clinical testing
Invitae RCV002515808 SCV003443235 uncertain significance RYR1-Related Disorders 2022-03-12 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1140 of the RYR1 protein (p.Arg1140Cys). This variant is present in population databases (rs193922776, gnomAD 0.01%). This missense change has been observed in individual(s) with malignant hyperthermia (PMID: 16917943). ClinVar contains an entry for this variant (Variation ID: 133126). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RYR1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Leiden Muscular Dystrophy (RYR1) RCV000119610 SCV000154517 not provided not provided no assertion provided not provided

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