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

dbSNP: rs118192178

Total submissions: 12

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