ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.7522C>T (p.Arg2508Cys)

dbSNP: rs118192178
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Total submissions: 12
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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 RCV002281900 SCV002570158 likely pathogenic Malignant hyperthermia, susceptibility to, 1 2023-05-20 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 2508 of the RYR1 protein, p.(Arg2508Cys). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in five unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, one of these individuals had 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_Moderate (PMID: 30236257, 16732084, 21157159, 27918309). A functional study in HEK293 cells shows an increased sensitivity to RYR1 agonists, (PMID: 27586648). As well, a knock-in mouse model supports pathogenicity of this variant demonstrating a malignant hyperthermia reaction in response to agonist, PS3_Strong (PMID:34257294). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. Another variant assessed as likely pathogenic occurs at this codon, p.(Arg2508His), PM5_Supporting. A REVEL score >0.85 (0.861) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS3_Strong, PS4_Moderate, PM5_Supporting, PP3_Moderate.
Eurofins Ntd Llc (ga) RCV000119718 SCV000230733 likely pathogenic not provided 2015-04-30 criteria provided, single submitter clinical testing
Invitae RCV000552166 SCV000660027 pathogenic RYR1-related disorder 2023-10-12 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 2508 of the RYR1 protein (p.Arg2508Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with central core disease and/or malignant hyperthermia susceptibility (PMID: 16621918, 16732084, 19685112, 21157159, 25747005). ClinVar contains an entry for this variant (Variation ID: 65981). 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. Experimental studies have shown that this missense change affects RYR1 function (PMID: 19685112, 26381711). This variant disrupts the p.Arg2508 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16621918, 16732084, 20142353, 26381711). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000624571 SCV000741781 pathogenic Inborn genetic diseases 2016-09-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
PreventionGenetics, part of Exact Sciences RCV000119718 SCV000852780 pathogenic not provided 2013-11-21 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000119718 SCV001249993 pathogenic not provided 2019-10-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV001198416 SCV001369350 likely pathogenic Congenital myopathy with fiber type disproportion 2020-03-20 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM2,PM5,PP2,PP3,PS4_MOD.
Kariminejad - Najmabadi Pathology & Genetics Center RCV001814037 SCV001755503 likely pathogenic Abnormality of the musculature 2021-07-10 criteria provided, single submitter clinical testing
Institute of Human Genetics, Heidelberg University RCV000056228 SCV002757811 likely pathogenic Central core myopathy 2022-07-04 criteria provided, single submitter clinical testing
GeneReviews RCV000056228 SCV000087317 pathologic Central core myopathy 2010-05-11 no assertion criteria provided curation Converted during submission to Pathogenic.
Leiden Muscular Dystrophy (RYR1) RCV000119718 SCV000154625 not provided not provided no assertion provided not provided
OMIM RCV001731347 SCV001977100 pathogenic King Denborough syndrome 2021-10-11 no assertion criteria provided literature only

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