Submissions for variant NM_000540.3(RYR1):c.14270G>A (p.Arg4757His)

gnomAD frequency: 0.00013  dbSNP: rs768360593

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV001450014	SCV001653564	uncertain significance	Malignant hyperthermia of anesthesia	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 histidine at codon 4757 of the RYR1 protein, p.(Arg4757His). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: .000159, a frequency consistent with pathogenicity for MHS. 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) (PMID: 30236257). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704). A REVEL score <0.50 (0.452) supports a benign status for this variant, BP4. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1_Supporting, BP4.
Eurofins Ntd Llc (ga)	RCV000721359	SCV000339056	uncertain significance	not provided	2016-01-20	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000293888	SCV000413016	uncertain significance	Neuromuscular disease, congenital, with uniform type 1 fiber	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000351106	SCV000413017	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000389289	SCV000413018	uncertain significance	Congenital multicore myopathy with external ophthalmoplegia	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000287938	SCV000413019	uncertain significance	Central core myopathy	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000721359	SCV000576933	uncertain significance	not provided	2020-10-09	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV000539271	SCV000659843	likely benign	RYR1-related disorder	2024-01-25	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000721359	SCV000852400	uncertain significance	not provided	2013-10-30	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000721359	SCV001715523	uncertain significance	not provided	2020-11-17	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000721359	SCV001747214	uncertain significance	not provided	2022-12-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002487228	SCV002780291	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	2021-08-13	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000721359	SCV003799297	uncertain significance	not provided	2022-11-23	criteria provided, single submitter	clinical testing	The RYR1 c.14270G>A; p.Arg4757His variant (rs768360593) is reported in the literature in an individual with a personal or family history of an MH episode (Miller 2018). This variant is also reported in ClinVar (Variation ID: 285857) and is found in the non-Finnish European population with an allele frequency of 0.01% (18/113532 alleles) in the Genome Aggregation Database. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS (Maclennan 2011). The arginine at codon 4757 is moderately conserved, but computational analyses predict that this variant is neutral (REVEL: 0.452). Due to limited information, the clinical significance of the p.Arg4757His variant is uncertain at this time. References: Maclennan DH et al. Mechanistic models for muscle diseases and disorders originating in the sarcoplasmic reticulum. Biochim Biophys Acta. 2011 May;1813(5):948-64. PMID: 21118704. Miller DM et al. Genetic epidemiology of malignant hyperthermia in the UK. Br J Anaesth. 2018 Oct;121(4):944-952. PMID: 30236257.
Revvity Omics, Revvity	RCV000721359	SCV003814419	uncertain significance	not provided	2022-01-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000351106	SCV004358224	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-05-01	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 4757 of the RYR1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a family affected with malignant hyperthermia susceptibility (PMID: 30236257). This variant has been identified in 25/251108 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000721359	SCV002035175	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000721359	SCV002037239	uncertain significance	not provided		no assertion criteria provided	clinical testing