Submissions for variant NM_000540.3(RYR1):c.14210G>A (p.Arg4737Gln)

dbSNP: rs193922868

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV003231155	SCV002047631	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 glutamine at codon 4737 of the RYR1 protein, p.(Arg4737Gln). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000009, a frequency consistent with pathogenicity for MHS. This variant has been reported in 14 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all 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:16163667, PMID:18564801, PMID:24433488, NZ MH investigation unit, MH Investigation Unit (MHIU), UHN, Toronto). This variant segregates with MHS in >6 meioses, PP1_Strong, (PMID:30236257 , PMID:18564801, MH Investigation Unit (MHIU), UHN, Toronto). However, in a different family two genotype positive/phenotype negative (IVCT-) individuals were identified, BS2_Moderate. Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate, (PMID:36208971). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Supporting (PMID: 21118704). A REVEL score >0.85 (0.89) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). Criteria implemented: PS3_Moderate, PS4, PM1_Supporting, PP1_Strong, PP3_Moderate, BS2_Moderate.
GeneDx	RCV000119503	SCV000567320	pathogenic	not provided	2022-12-02	criteria provided, single submitter	clinical testing	Previously reported, using alternate nomenclature R4893Q, in association with malignant hyperthermia in multiple unrelated individuals (Monnier et al., 2005; Robinson et al., 2006; Gillies et al., 2008; Carpenter et al., 2009); Published functional studies demonstrate a damaging effect (Gomez et al., 2016); 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: 16917943, 27558158, 25960145, 27663056, 28326467, 16163667, 30788618, 19648156, 30236257, 18564801)
PreventionGenetics, part of Exact Sciences	RCV000119503	SCV000852398	pathogenic	not provided	2019-02-19	criteria provided, single submitter	clinical testing
Invitae	RCV001380753	SCV001578910	pathogenic	RYR1-related disorder	2023-05-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 4737 of the RYR1 protein (p.Arg4737Gln). This variant is present in population databases (rs193922868, gnomAD 0.0009%). This missense change has been observed in individuals with malignant hyperthermia (PMID: 16163667, 18564801, 19648156, 25960145). ClinVar contains an entry for this variant (Variation ID: 133061). 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: 27558158). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000119503	SCV002019970	pathogenic	not provided	2019-03-25	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000119503	SCV002051477	pathogenic	not provided	2020-11-16	criteria provided, single submitter	clinical testing	PS3, PP3, PM1, PM2, PM5
Fulgent Genetics, Fulgent Genetics	RCV002498548	SCV002811462	likely pathogenic	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome	2021-07-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV003231155	SCV004358222	pathogenic	Malignant hyperthermia, susceptibility to, 1	2023-09-05	criteria provided, single submitter	clinical testing	This variant replaces arginine with glutamine at codon 4737 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). This variant is located in a region of the RYR1 protein considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). A functional study has shown the mutant protein to exhibit hypersensitivity to an RYR1 agonist in calcium release assays (PMID: 36208971). This variant has been reported in over ten unrelated individuals affected with malignant hyperthermia susceptibility (PMID: 16163667, 18564801, 24433488, 30236257, 36208971). This variant has been shown to segregate with malignant hyperthermia susceptibility in 6 meioses in one family (PMID:18564801) and reported to segregate with disease in additional families (PMID: 30236257). Two related individuals who carry this variant have been reported to test negative in in vitro contracture tests (PMID: 30236257). This variant has been identified in 1/251402 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg4737Trp, is known to be associated with malignant hyperthermia susceptibility (ClinVar variation ID: 133060), indicating that arginine at this position is important for RYR1 protein function. Based on the available evidence, this variant is classified as Pathogenic.
All of Us Research Program, National Institutes of Health	RCV003231155	SCV004831690	pathogenic	Malignant hyperthermia, susceptibility to, 1	2023-07-11	criteria provided, single submitter	clinical testing	The c.14210G>A (p.Arg4737Gln) variant of the RYR1 gene replaces arginine with glutamine at codon 4737 of the RYR1 protein (p.Arg4737Gln). This missense change has been observed in more than 10 individuals with personal or family history of a malignant hyperthermia reaction, positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) (PMID: 16163667, 18564801, 19648156, 25960145). This variant segregates with malignant hyperthermia syndrome (MHS) in more than 6 meioses (PMID:30236257, 18564801). However, in a different family two genotype positive/phenotype negative (IVCT-) individuals were identified. This variant is located at a mutational hot spot region that contributes to MHS (PMID: 21118704). Experimental studies have shown that this missense change affects RYR1 function (PMID: 27558158). Computational prediction (REVEL=0.89 PMID: 27666373) suggests that this variant may have deleterious impact on protein structure and function. Alteration affecting the same amino acid, c.14209C>T (p.Arg4737Trp), was classified as likely pathogenic by the expert panel (ClinVar ID:133060). Therefore, this c.14210G>A (p.Arg4737Gln) variant of RYR1 gene is classified as pathogenic.
Leiden Muscular Dystrophy (RYR1)	RCV000119503	SCV000154410	not provided	not provided		no assertion provided	not provided