Submissions for variant NM_000540.3(RYR1):c.3127C>T (p.Arg1043Cys)

gnomAD frequency: 0.00002  dbSNP: rs111272095

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV000148799	SCV001810104	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-04-06	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 1043 of the RYR1 protein, p.Arg1043Cys. This variant has been reported in an individual with a personal or family history of an MH episode and 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), however, this individual also had a second RYR1 variant classified as pathogenic p.Arg2336His (PMID:19191329). Both the presence of a pathogenic RYR1 variant and the high MAF in the AMR population in gnomAD preclude the use of PS4. No functional studies were identified for this variant. A REVEL score >0.85 (0.936) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PP3_Moderate.
Eurofins Ntd Llc (ga)	RCV000119607	SCV000228120	uncertain significance	not provided	2014-07-11	criteria provided, single submitter	clinical testing
Invitae	RCV000546583	SCV000659912	uncertain significance	RYR1-related disorder	2022-07-19	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 1043 of the RYR1 protein (p.Arg1043Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed to co-occur in individuals with a different variant in RYR1 that has been determined to be pathogenic (PMID: 19191329, 23558838, 30155738), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 133124). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences	RCV000119607	SCV000852561	uncertain significance	not provided	2013-11-19	criteria provided, single submitter	clinical testing
Mendelics	RCV000148799	SCV001141058	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-06-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824614	SCV002074334	uncertain significance	not specified	2022-01-19	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.3127C>T (p.Arg1043Cys) results in a non-conservative amino acid change located in the Ryanodine receptor Ryr domain (IPR003032) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.9e-05 in 203518 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3127C>T has been reported in the literature in individuals affected with Malignant Hyperthermia Susceptibility and other RYR1-related myopathy, however it was shown co-occuring with other RYR1 pathogenic variants: c.7007G>A, p.Arg2336His (ClinVar:133174, pathogenic) (Levano_2009, Brandom_2013, Kushnir_2020, internal testing) or c.1589G>A, p.Arg530His (ClinVar:133101, VUS/likely pathogenic/pathogenic)(Herman_2021, Kushnir_2020), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters, including one expert panel, have assessed this variant since 2014: two have classified the variant as of uncertain significance and one as benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV002498550	SCV002791005	uncertain significance	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome	2022-02-08	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000148799	SCV004820798	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-01-03	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 1043 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two families/individuals affected with malignant hyperthermia susceptibility, these individuals also carried a known pathogenic variant in the RYR1 gene that could explain the observed phenotype (PMID: 19191329, 23558838). This variant has been identified in 6/203518 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Leiden Muscular Dystrophy (RYR1)	RCV000119607	SCV000154514	not provided	not provided		no assertion provided	not provided
CSER _CC_NCGL, University of Washington	RCV000148799	SCV000190537	likely benign	Malignant hyperthermia, susceptibility to, 1	2014-06-01	no assertion criteria provided	research