Submissions for variant NM_000540.3(RYR1):c.1598G>A (p.Arg533His)

gnomAD frequency: 0.00029  dbSNP: rs144336148

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV000148808	SCV001816161	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-04-10	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 533 of the RYR1 protein, p.(Arg533His). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.00044, a frequency consistent with pathogenicity for MHS. This variant has been reported in 3 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 2 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), (PMID:30236257, PMID:16732084). However, the high MAF in the AFR population in gnomAD precludes the use of PS4. Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate, (PMID:23459219). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.824 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS3_Moderate, PM1.
Eurofins Ntd Llc (ga)	RCV000119578	SCV000203448	uncertain significance	not provided	2016-06-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000543445	SCV000659869	uncertain significance	RYR1-related disorder	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 533 of the RYR1 protein (p.Arg533His). This variant is present in population databases (rs144336148, gnomAD 0.06%). This missense change has been observed in individual(s) with clinical features of RYR1-related conditions (PMID: 10484775). ClinVar contains an entry for this variant (Variation ID: 133103). 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: 23459219). 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	RCV000543445	SCV000852483	uncertain significance	RYR1-related disorder	2023-05-23	criteria provided, single submitter	clinical testing	The RYR1 c.1598G>A variant is predicted to result in the amino acid substitution p.Arg533His. This variant has been reported in several individuals who have had malignant hyperthermia (MH) events or are MH-susceptible via the in vitro muscle contracture test (Brandt et al. 1999. PubMed ID: 10484775; Robinson et al. 2006. PubMed ID: 16917943; Ibarra et al. 2006. PubMed ID: 16732084; Miller et al. 2018. PubMed ID: 30236257). A different substitution at the same amino acid (p.Arg533Cys) was reported to segregate with in vitro contracture test results in a large three generation family (Tammaro et al. 2003. PubMed ID: 12709367). The c.1598G>A (p.Arg533His) variant was reported to affect Ca++ channel function in an in vitro assay (Sato et al. 2013. PubMed ID: 23459219). Exon 15 is a hotspot in the RYR1 gene for pathogenic MH variants. However, the c.1598G>A (p.Arg533His) variant is reported in 0.04% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-38946112-G-A) and at PreventionGenetics we have observed this variant in many individuals with no indication of MH related events (internal data). An expert ClinGen panel interprets the c.1598G>A variant as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/133103/). Although we suspect this variant could contribute to MHS, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000853506	SCV000996439	likely pathogenic	Central core myopathy	2019-07-12	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000119578	SCV001151809	likely pathogenic	not provided	2024-08-01	criteria provided, single submitter	clinical testing	RYR1: PM1, PM5, PS4:Moderate, PS3:Supporting
GeneDx	RCV000119578	SCV001782464	likely pathogenic	not provided	2024-10-31	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect with increased sensitivity to a RYR1 agonist compared to wild-type controls (PMID: 23459219); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10484775, 24055113, 25637381, 27147545, 30236257, 11668625, 31301762, 33767344, 32381029, 32919876, Kanzaki2022[Paper], 35718563, 34890165, 16732084, 23459219, 30499100, 16084090, 16917943)
Institute of Human Genetics, University of Leipzig Medical Center	RCV000148808	SCV001950094	likely pathogenic	Malignant hyperthermia, susceptibility to, 1	2024-07-05	criteria provided, single submitter	clinical testing	Criteria applied: PS4_MOD,PS3_MOD,PM5,PM1_SUP,PP3
AiLife Diagnostics, AiLife Diagnostics	RCV000119578	SCV002502822	likely pathogenic	not provided	2021-12-16	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV000148808	SCV002503841	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-03-30	criteria provided, single submitter	clinical testing	This sequence change is predicted to replace arginine with histidine at codon 533 of the RYR1 protein (p.(Arg533His)). The arginine residue is very highly conserved (100 vertebrates, UCSC), and located in the IP3 receptor type 1 binding core, domain 2. There is a small physicochemical difference between arginine and histidine. The variant is present in a large population cohort at a frequency of 0.03% (rs144336148, gnomAD v3.1). The variant has been reported in two affected individuals with malignant hyperthermia susceptibility in heterozygous form (PMID: 30236257) and in homozygous form in an individual who was also homozygous for another RYR1 variant (PMID: 16732084). Experimental studies in HEK-293 cells have demonstrated that this missense variant affects calcium channel function in vitro (PMID: 23459219). This missense variant is associated with a positive in vitro contracture test for malignant hyperthermia susceptibility (Royal Melbourne Hospital). Multiple lines of computational evidence have conflicting predictions for the missense substitution (3/6 algorithms predict deleterious). A missense variant at the same codon with a large physicochemical difference, p.(Arg533Cys), is listed as a diagnostic mutation by the European Malignant Hyperthermia Group. The p.(Arg533His) missense variant is listed as a diagnostic mutation by the European Malignant Hyperthermia Group, but as a variant of uncertain significance by ClinGen. Based on the classification guideline RMH Modified ACMG Guidelines v1.3.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. The following criteria are met: PS3, PP4.
MGZ Medical Genetics Center	RCV000148808	SCV002580161	likely pathogenic	Malignant hyperthermia, susceptibility to, 1	2022-06-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002505054	SCV002814496	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	2022-03-28	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000119578	SCV003813052	uncertain significance	not provided	2023-08-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003993812	SCV004813651	uncertain significance	not specified	2024-02-19	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.1598G>A (p.Arg533His) results in a non-conservative amino acid change located in the RIH domain (IPR000699) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 251492 control chromosomes. c.1598G>A has been reported in the literature in at-least three individuals affected with malignant hyperthermia (Ibarra_2006, Miller_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Myopathy, RYR1-Associated. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in increased sensitivity to agonist in HEK293 cells (Sato_2013). The following publications have been ascertained in the context of this evaluation (PMID: 16732084, 30236257, 23459219). ClinVar contains an entry for this variant (Variation ID: 133103). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
All of Us Research Program, National Institutes of Health	RCV000148808	SCV004820751	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 533 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). A functional study has shown cells expressing this variant have increased sensitivity to RYR1 agonists compared to cells expressing wild-type RYR1 (PMID: 23459219). This variant has been reported at least two families affected with malignant hyperthermia susceptibility (PMID: 30236257). This variant has been identified in 32/282858 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same codon, c.1597C>T (p.Arg533Cys), is a well-documented pathogenic variant (ClinVar Variation ID: 133102), indicating that Arg at this position may be important for RYR1 protein function. 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)	RCV000119578	SCV000154485	not provided	not provided		no assertion provided	not provided
CSER _CC_NCGL, University of Washington	RCV000148808	SCV000190547	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2014-06-01	no assertion criteria provided	research