Submissions for variant NM_000540.3(RYR1):c.1021G>A (p.Gly341Arg)

dbSNP: rs121918592

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV000013836	SCV001816165	pathogenic	Malignant hyperthermia, susceptibility to, 1	2021-03-18	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 341 of the RYR1 protein p.(Gly341Arg), c.1021G>A. This variant is not present in a large population database (gnomAD). This variant has been reported in 71 unrelated probands 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 ( PMID:30236257, PMID:16163667, PMID: 8012359 and others). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (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 66 individuals, PP1_Strong ( PMID: 8012359, PMID:9106529, PMID:17710899 and others). A REVEL score > 0.85 supports pathogenicity,PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). Criteria implemented: PS4, PS3_Moderate, PM1, PP1_Strong, PP3_Moderate, BS2_Moderate.
Eurofins Ntd Llc (ga)	RCV000119406	SCV000225241	likely pathogenic	not provided	2014-09-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000655541	SCV000777472	pathogenic	RYR1-related disorder	2024-01-13	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 341 of the RYR1 protein (p.Gly341Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with malignant hyperthermia (PMID: 8012359, 8825043, 19648156, 24433488). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12969). 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, 12732639). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV000119406	SCV000852200	pathogenic	not provided	2018-03-15	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000119406	SCV002019916	pathogenic	not provided	2019-05-06	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000119406	SCV002770437	pathogenic	not provided	2022-06-23	criteria provided, single submitter	clinical testing	This variant has been identified in multiple unrelated individuals with susceptibility to malignant hyperthermia (MHS) and associates with MHS in multiple families. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as G342R. Assessment of experimental evidence suggests this variant results in abnormal protein function. Variant increased sensitivity to RYR1 activators (PMID:26115329, 9334205, 12732639).
Color Diagnostics, LLC DBA Color Health	RCV000013836	SCV004357272	pathogenic	Malignant hyperthermia, susceptibility to, 1	2023-04-18	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 341 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies using HEK293 cells and dyspedic myotubes have shown this variant increases sensitivity to RYR1 agonists compared to wild type RYR1 (PMID: 9334205, 9873004, 12732639, 26115329). This variant has been reported in over 50 families and/or individuals affected with malignant hyperthermia (PMID: 8825043, 9106529, 16163667, 18564801, 19648156, 24433488, 30236257). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Molecular Genetics, Royal Melbourne Hospital	RCV000013836	SCV004812872	pathogenic	Malignant hyperthermia, susceptibility to, 1	2023-11-05	criteria provided, single submitter	clinical testing	This sequence change in RYR1 is predicted to replace glycine with arginine at codon 341, p.(Gly341Arg). The glycine residue is highly conserved (100 vertebrates, UCSC), and is located in exon 11 in the N-terminal region, amino acids 1-552, which is defined as a mutational hotspot. There is a large physicochemical difference between glycine and arginine. This variant is absent from the population database gnomAD v2.1 and v3.1. This variant has been reported in multiple families with malignant hyperthermia susceptibility (MHS) confirmed by in vitro contracture testing (IVCT) and/or a personal/family history of an anaesthetic reaction, and it segregates with MHS in multiple families (PMID: 30236257). This variant has been observed in at least one family with a negative IVCT (PMID: 30236257). The variant demonstrates significantly enhanced sensitivity to calcium release in HEK293 cells indicating that this variant impacts protein function (PMID: 9334205, 26115329). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.864). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PS4, PP1_Strong, PM1, PP3_Moderate, PS3_Moderate, BS2_Moderate.
All of Us Research Program, National Institutes of Health	RCV000013836	SCV004820735	pathogenic	Malignant hyperthermia, susceptibility to, 1	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 341 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies using HEK293 cells and dyspedic myotubes have shown this variant increases sensitivity to RYR1 agonists compared to wild type RYR1 (PMID: 9334205, 9873004, 12732639, 26115329). This variant has been reported in over 50 families and/or individuals affected with malignant hyperthermia (PMID: 8825043, 9106529, 16163667, 18564801, 19648156, 24433488, 30236257). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
GeneDx	RCV000119406	SCV005324903	pathogenic	not provided	2022-05-26	criteria provided, single submitter	clinical testing	Published functional studies suggest that the variant increases RYR1 channel sensitivity to caffeine and halothane and resistance to channel inactivation (PMID: 12732639, 9334205); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19648156, 29101530, 9334205, 9873004, 30236257, 12124989, 31206373, 8825043, 35428369, 12732639, 8012359, 33057194, 26115329, 35982159)
OMIM	RCV000013836	SCV000034083	risk factor	Malignant hyperthermia, susceptibility to, 1	1998-10-01	no assertion criteria provided	literature only
Leiden Muscular Dystrophy (RYR1)	RCV000119406	SCV000154313	not provided	not provided		no assertion provided	not provided