Submissions for variant NM_000540.3(RYR1):c.742G>C (p.Gly248Arg)

dbSNP: rs1801086

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV002281946	SCV002570151	pathogenic	Malignant hyperthermia, susceptibility to, 1	2022-09-08	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 glycine with arginine at codon 248 of the RYR1 protein c.742G>C; p.(Gly248Arg). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.00005), a frequency consistent with pathogenicity for MHS. This variant has been reported in four unrelated individuals who have a personal or family history of a malignant hyperthermia reaction and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted), PS4_Moderate (PMID:30236257, PMID:19346234). This variant segregates with MHS in five individuals/families, PP1_Moderate (PMID:30236257, PMID:19346234, PMID:18564801). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:26115329, PMID:27857962). Another variant assessed as pathogenic occurs at this codon, c.742G>A; p.(Gly248Arg), PS1. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PS1 (PMID: 21118704).A REVEL score > 0.85 supports pathogenicity, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS4_Moderate, PS3_Moderate, PM1_Supporting, PS1, PP1_Moderate, PP3_Moderate.
GeneDx	RCV000119714	SCV000329914	pathogenic	not provided	2024-05-30	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 7849712, 31301762, 32231684, 20461000, 23422674, 25525159, 24627108, 19346234, 27147545, 9334205, 9873004, 33564012, 26115329, 6917943, 15448513, 33767344, 27857962, 23919265, 23558838, 12565913, 11575529, 36245440, 21795085, 30236257, 18564801)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000704587	SCV000833540	pathogenic	RYR1-related disorder	2024-07-24	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 248 of the RYR1 protein (p.Gly248Arg). This variant is present in population databases (rs1801086, gnomAD 0.005%). This missense change has been observed in individuals with autosomal dominant malignant hyperthermia susceptibility (PMID: 1354642, 11575529, 15448513, 18564801, 19648156, 23558838). ClinVar contains an entry for this variant (Variation ID: 133203). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR1 protein function. Experimental studies have shown that this missense change affects RYR1 function (PMID: 6917943, 9334205, 9873004, 12565913, 23919265, 27857962). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV000119714	SCV000852774	pathogenic	not provided	2013-11-19	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000119714	SCV002506287	pathogenic	not provided	2022-02-04	criteria provided, single submitter	clinical testing	The RYR1 c.742G>C; p.Gly248Arg variant (rs1801086) is published in the literature in several individuals affected with malignant hyperthermia (MH), confirmed by caffeine/halothane contracture test (Brandom 2013, Gillies 2008, Sambuughin 2001, Sei 2004) and is considered diagnostic for MH by the European Malignant Hyperthermia group. The variant is described as pathogenic by several sources in the ClinVar database (Variation ID: 133203) and is only found on 4 alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The glycine at codon 248 is highly conserved and computational analyses predict that this variant is deleterious (REVEL: 0.883). In support of this prediction, functional studies show variants in this region cause hyperactive RYR1 channels (Tong 1997). Based on available information, this variant is classified as pathogenic. References: Brandom BW et al. Ryanodine receptor type 1 gene variants in the malignant hyperthermia-susceptible population of the United States. Anesth Analg. 2013 May;116(5):1078-86. Gillies RL et al. Identification of genetic mutations in Australian malignant hyperthermia families using sequencing of RYR1 hotspots. Anaesth Intensive Care. 2008 May;36(3):391-403. Sambuughin N et al. North American malignant hyperthermia population: screening of the ryanodine receptor gene and identification of novel mutations. Anesthesiology. 2001 Sep;95(3):594-9. Sei Y et al. Malignant hyperthermia in North America: genetic screening of the three hot spots in the type I ryanodine receptor gene. Anesthesiology. 2004 Oct;101(4):824-30. Tong J et al. Caffeine and halothane sensitivity of intracellular Ca2+ release is altered by 15 calcium release channel (ryanodine receptor) mutations associated with malignant hyperthermia and/or central core disease. J Biol Chem. 1997 Oct 17;272(42):26332-9.
CeGaT Center for Human Genetics Tuebingen	RCV000119714	SCV004011049	pathogenic	not provided	2023-05-01	criteria provided, single submitter	clinical testing	RYR1: PM1:Strong, PS1, PS3:Moderate, PP1, PS4:Supporting
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	RCV003330082	SCV004037136	pathogenic	Autism spectrum disorder due to AUTS2 deficiency		criteria provided, single submitter	not provided
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV002281946	SCV005397881	pathogenic	Malignant hyperthermia, susceptibility to, 1	2022-11-03	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV002281946	SCV005416665	pathogenic	Malignant hyperthermia, susceptibility to, 1		criteria provided, single submitter	clinical testing	PS1_Moderate+PS4_Moderate+PP1_Moderate+PM1+PS3_Moderate
All of Us Research Program, National Institutes of Health	RCV002281946	SCV005430457	pathogenic	Malignant hyperthermia, susceptibility to, 1	2024-09-13	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 248 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies in HEK293 cells have shown that cells expressing this variant have increased sensitivity to caffeine, halothane, and 4-CmC compared to cells expressing wild-type RYR1 (PMID: 15448513, 20461000, 27857962, 9334205). This variant has been reported in families and individuals affected with malignant hyperthermia susceptibility (PMID: 18564801, 19346234, 23558838, 30236257). This variant has been shown to segregate with disease in 1 family, this family carried a second RYR1 variant of uncertain significance in cis (PMID: 19346234, 30236257). This variant has been identified in 4/282572 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Leiden Muscular Dystrophy (RYR1)	RCV000119714	SCV000154621	not provided	not provided		no assertion provided	not provided