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

dbSNP: rs1801086

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV000013831	SCV002570141	likely pathogenic	Malignant hyperthermia, susceptibility to, 1	2023-04-07	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, p.(Gly248Arg), c.742G>A. This variant is not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in 10 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 8 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 (PMID:30236257, PMID:23558838, PMID:11575529, PMID:1354642). This variant has been identified in 1 individual with negative IVCT/CHCT results, BS2_Moderate. Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate, (PMID:9334205, PMID:26115329). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). This variant segregates with MHS in three individuals, PP1 (PMID:1354642, PMID:19454545). A REVEL score >0.85 (0.889) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Likely Pathogenic, (PMID: 29300386). Criteria implemented: PS3_Moderate, PS4, PM1, PP1, PP3_Moderate, BS2_Moderate.
PreventionGenetics, part of Exact Sciences	RCV000119713	SCV000852773	pathogenic	not provided	2015-10-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851834	SCV002200229	pathogenic	RYR1-related disorder	2024-01-02	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 not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with malignant hyperthermia susceptibility (PMID: 1354642, 11575529, 15448513, 18564801, 19648156, 23558838). ClinVar contains an entry for this variant (Variation ID: 12965). 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: 9334205, 9873004, 27857962). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000013831	SCV002764860	pathogenic	Malignant hyperthermia, susceptibility to, 1	2020-11-09	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017237	SCV004848362	likely pathogenic	Malignant hyperthermia of anesthesia	2020-06-11	criteria provided, single submitter	clinical testing	Two different single nucleotide variants (c.742G>C and c.742G>A) resulting in the same missense change, p.Gly248Arg, have been reported in at least 14 heterozygous individuals with malignant hyperthermia susceptibility with 9 segregations in affected relatives (Brandom 2013, Broman 2015, Broman 2009, Abolkhair 2011, Carpenter 2009, Robinson 2006, Gillard 1992, Gillies 2008, Miller 2018, Sei 2004). This variant was absent from large population studies. In one study, 3 nonsegregations (genotype negative, phenotype positive) were observed in one family; though, limited details on the affected relatives were provided (Miller 2018) and in vitro contracture testing sometimes results in false positives. This variant is reported in ClinVar by the PharmGKB expert panel as a known malignant hyperthermia variant with evidence level 1A (Variation ID 12965). One in vitro functional study suggested abnormal protein function (Sato 2010). In vitro studies investigating a nearby variant, Gly249Arg, found caffeine and halothane sensitivity of intracellular Ca2+ release in one study, and similar resting cytoplasmic Ca2+ concentration in another study (Tong 1997, 1999). Computational prediction tools and conservation analysis suggest an impact to the protein. In summary, while there is some conflicting evidence in the reported nonsegregations, there is significant evidence to support that this variant is likely pathogenic for autosomal dominant malignant hyperthermia susceptibility. ACMG/AMP criteria applied: PS4_Moderate, PP1_Strong, PM2, PS3_Supporting, PP3, BS4_Supporting.
OMIM	RCV000013831	SCV000034078	risk factor	Malignant hyperthermia, susceptibility to, 1	1992-08-01	no assertion criteria provided	literature only
Leiden Muscular Dystrophy (RYR1)	RCV000119713	SCV000154620	not provided	not provided		no assertion provided	not provided