Submissions for variant NM_000540.3(RYR1):c.10043G>A (p.Arg3348His)

gnomAD frequency: 0.00001  dbSNP: rs193922834

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV001450000	SCV001653550	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 histidine at codon 3348 of the RYR1 protein, p.(Arg3348His). This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, both 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_Supporting (PMID:15731587, PMID:25735680). No functional studies were identified for this variant. A REVEL score of 0.705 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting.
Fulgent Genetics, Fulgent Genetics	RCV002492407	SCV002796417	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	2022-03-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000119399	SCV003813034	uncertain significance	not provided	2022-01-16	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001450000	SCV004820965	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-05-17	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 3348 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 not been reported in two individuals affected with malignant hyperthermia, including one who also carried additional VUS RYR1 co-variants (PMID: 15731587, 25735680). This variant has been identified in 5/282378 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786374	SCV005399109	uncertain significance	Central core myopathy	2022-03-31	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene. Variants exerting a loss of function effect are associated with autosomal recessive minicore myopathy with external ophthalmoplegia (MIM#255320), central core disease and neuromuscular disease, congenital, with uniform type 1 fiber (MIM#117000). Gain of function is associated with autosomal dominant King-Denborough syndrome (MIM#619542), malignant hyperthermia susceptibility (MIM#145600), central core disease and neuromuscular disease, congenital, with uniform type 1 fiber (MIM#117000) (PMID: 23919265, 27855725, 27858745, 30155320). (I) 0108 - This gene is associated with both recessive and dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2: 5 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (19 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has mostly been reported in the context of malignant hyperthermia and has been classified as a VUS by ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel (PMID: 15731587, 25735680). There is a single report of it being identified in an individual with neuromuscular disorder, however additional details such as clinical information and zygosity were not provided (PMID: 32528171). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Leiden Muscular Dystrophy (RYR1)	RCV000119399	SCV000154306	not provided	not provided		no assertion provided	not provided
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000119399	SCV001808316	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000119399	SCV001951165	uncertain significance	not provided		no assertion criteria provided	clinical testing