Submissions for variant NM_000540.3(RYR1):c.1589G>A (p.Arg530His)

gnomAD frequency: 0.00003  dbSNP: rs111888148

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV000148805	SCV001816168	likely 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 Histidine at codon 530 of the RYR1 protein, p.(Arg530His). The maximum allele frequency for this variant among the six major gnomAD populations is AMR: 0.000145, a frequency consistent with pathogenicity for MHS. This variant has been reported in five 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_Moderate (PMID:19191329, PMID:19191333, PMID:30236257, PMID:35718563). A functional study was published for this variant looking at acidification rates in B-lymphocytes, this assay is not considered a standard assay by the ClinGen RYR1 VCEP for MHS (PMID:27646467). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID:21118704). This variant segregates with MHS in 2 individuals (PMID:19191333). A REVEL score >0.85 supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic. Criteria implemented: PS4_Moderate, PM1, PP3_Moderate.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000655554	SCV000777485	pathogenic	RYR1-related disorder	2024-11-20	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 530 of the RYR1 protein (p.Arg530His). This variant is present in population databases (rs111888148, gnomAD 0.01%). This missense change has been observed in individuals with autosomal dominant malignant hyperthermia susceptibility (PMID: 19191329, 19191333, 30236257). It has also been observed to segregate with disease in related individuals. This variant has been reported in individual(s) with clinical features of autosomal recessive congenital myopathy (PMID: 26578207); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 133101). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RYR1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RYR1 function (PMID: 19191333, 27646467). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000119576	SCV001248780	likely pathogenic	not provided	2024-08-01	criteria provided, single submitter	clinical testing	RYR1: PM1, PS4:Moderate, PM5:Supporting, PS3:Supporting
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001249073	SCV001423024	pathogenic	King Denborough syndrome	2020-01-29	criteria provided, single submitter	curation	The p.Arg530His variant in RYR1 has been reported in at least 7 individuals, including 1 Turkish and 1 Swiss individual, with King-Denborough syndrome, segregated with disease in 3 affected relatives from 1 family (PMID: 19191329, 30236257, 30155738, 26578207, 19191333, 16917943), and has been identified in 0.01446% (5/34590) of Latino chromosomes, 0.006152% (1/16256) of African chromosomes, and 0.005274% (6/113770) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs111888148). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population and individuals with this disease are clinically indistinguishable from the general population unless given anesthesia (PMID: 9199552). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a dominant frequency for a disease with clinical variability or reduced penetrance. This variant has also been reported in ClinVar as a VUS, pathogenic, and likely pathogenic variant (Variation ID: 133101). In vitro functional studies provide some evidence that the p.Arg530His variant may impact protein function and may be partially rescued by a RYR1 antagonist (PMID: 19191333). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional variant, resulting in a different amino acid change at the same position, p.Arg530Leu, has been reported as a VUS in association with disease in ClinVar (Variation ID: 212096). The p.Arg530His is located in a region of RYR1 that is essential to regulating the sensitivity of a calcium channel, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 16084090). In summary, this variant meets criteria to be classified as pathogenic for King-Denborough syndrome in an autosomal dominant manner based on in vitro functional studies, population data, and multiple occurrences of affected individuals with this variant reported in the literature. ACMG/AMP Criteria applied: PS3, PM2, PS4_Moderate, PM1, PP3, PP1 (Richards 2015).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001449797	SCV001653080	likely pathogenic	Malignant hyperthermia of anesthesia	2020-03-28	criteria provided, single submitter	clinical testing	The p.Arg530His variant in RYR1 has been reported in 3 individuals with malignant hyperthermia (MH) and segregated with disease in 2 affected members from 1 family (Zullo 2009 PMID: 19191333, Levano 2009 PMID: 19191329, Miller 2018 PMID: 30236257). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 133101) and has been identified in 0.005% (6/113770) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies support an impact on the protein (Zullo 2009 PMID: 19191333, Hoppe 2016 PMID: 27646467), and computational prediction tools and conservation analysis are consistent with pathogenicity. In addition, this variant is located within the intracellular calcium-release channel domain, which is enriched with pathogenic variation and is considered a critical functional domain (Tilgen 2001 PMID: 11741831). Moreover, this variant has been classified as a diagnostic mutation by the European Malignant Hyperthermia Group (EMHG; https://www.emhg.org/diagnostic-mutations). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant MH. ACMG/AMP criteria applied: PP3, PS3_Moderate, PS4_Supporting, PM1.
GeneDx	RCV000119576	SCV001774088	pathogenic	not provided	2023-12-13	criteria provided, single submitter	clinical testing	Identified in the heterozygous state in association with malignant hyperthermia in published literature (PMID: 27646467, 19191333); Identified in an infant with malignant hyperthermia who harbored a second pathogenic RYR1 variant on the opposite allele (in trans) (PMID: 33625594); Published functional studies demonstrate that this variant results in altered channel function as compared to controls (PMID: 19191333, 32236737); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27147545, 33767344, 16917943, 19191329, 25637381, 30236257, 30155738, 19191333, 32236737, 34426522, 31589614, 31301762, 34849273, 33146414, 30291343, 27646467, 33625594, 26578207, 37787745)
Institute of Human Genetics, University of Leipzig Medical Center	RCV000148805	SCV001934463	likely pathogenic	Malignant hyperthermia, susceptibility to, 1	2023-07-12	criteria provided, single submitter	clinical testing	Criteria applied: PS4,PS3_SUP,PM2_SUP,PP3
Revvity Omics, Revvity	RCV000119576	SCV002019963	likely pathogenic	not provided	2023-07-28	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000119576	SCV002502744	likely pathogenic	not provided	2021-12-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001449797	SCV002571839	pathogenic	Malignant hyperthermia of anesthesia	2022-08-07	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.1589G>A (p.Arg530His) results in a non-conservative amino acid change located in the RIH domain (IPR000699) 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 5.6e-05 in 251494 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RYR1 causing Malignant Hyperthermia Susceptibility (5.6e-05 vs 8.8e-05), allowing no conclusion about variant significance. c.1589G>A has been reported in the literature as a heterozygous/compound heterozygous genotype in individuals affected with Malignant Hyperthermia Susceptibility or Neuromuscular Disease (example, Levano_2009, Zullo_2009, Todd_2015, Miller_2018, Kushnir_2020, Herman_2021, Tsutsumi_2021). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function reporting increased acidification rate of lymphoblastoid cells and immortalized B-lymphocytes in response to 4-chloro-mcresol (4-CmC) (example, Zullo_2009, Hoppe_2016). Multiple clinical diagnostic laboratories and an expert panel (ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a majority consensus as pathogenic/likely pathogenic (n=9) (VUS, n=2 to include the expert panel). Based on the evidence outlined above, the variant was classified as pathogenic.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000119576	SCV004026377	likely pathogenic	not provided	2021-10-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000148805	SCV004041474	pathogenic	Malignant hyperthermia, susceptibility to, 1	2023-08-30	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000119576	SCV004564554	likely pathogenic	not provided	2024-08-08	criteria provided, single submitter	clinical testing	The RYR1 c.1589G>A; p.Arg530His variant (rs111888148) is reported in the literature in multiple individuals and families affected with malignant hyperthermia (Levano 2009, Miller 2018, Mungunsukh 2019, Robinson 2006, Tsutsumi 2021, Zullo 2009). This variant is found in the general population with an overall allele frequency of 0.006% (14/251,494 alleles) in the Genome Aggregation Database. This variant occurs in the functionally important N-terminal domain, and computational analyses predict that this variant is deleterious (REVEL: 0.93). Functional assays indicate lymphoblastoid cell lines exhibit increased acidification in response to 4-chloro-m-cresol compared to cells expressing wildtype RYR1 (Zullo 2009), although this is not considered a standard assay. Based on available information, this variant is considered to be likely pathogenic. References: Levano S et al. Increasing the number of diagnostic mutations in malignant hyperthermia. Hum Mutat. 2009 Apr;30(4):590-8. PMID: 19191329. Miller DM et al. Genetic epidemiology of malignant hyperthermia in the UK. Br J Anaesth. 2018 Oct;121(4):944-952. PMID: 30236257. Mungunsukh O et al. Estimating prevalence of malignant hyperthermia susceptibility through population genomics data. Br J Anaesth. 2019 Sep;123(3):e461-e463. PMID: 31301762. Robinson R et al. Mutations in RYR1 in malignant hyperthermia and central core disease. Hum Mutat. 2006 Oct;27(10):977-89. PMID: 16917943. Tsutsumi YM et al. Malignant hyperthermia in a 16-day-old infant with congenital diaphragmatic hernia: a case report. J Anesth. 2021 Apr;35(2):311-314. PMID: 33625594. Zullo A et al. Functional characterization of ryanodine receptor (RYR1) sequence variants using a metabolic assay in immortalized B-lymphocytes. Hum Mutat. 2009 Apr;30(4):E575-90. PMID: 19191333.
Ambry Genetics	RCV004658970	SCV005161774	likely pathogenic	Inborn genetic diseases	2024-04-30	criteria provided, single submitter	clinical testing	The c.1589G>A (p.R530H) alteration is located in exon 15 (coding exon 15) of the RYR1 gene. This alteration results from a G to A substitution at nucleotide position 1589, causing the arginine (R) at amino acid position 530 to be replaced by a histidine (H). Based on data from gnomAD, the A allele has an overall frequency of 0.006% (14/251494) total alleles studied. The highest observed frequency was 0.016% (1/6140) of Other alleles. This variant was reported in multiple individuals, and was shown to segregate with disease in one family, with a reported malignant hyperthermia (MH) event, a positive IVCT, and/or a family history of MH (Levano, 2009; Zullo, 2009; Miller, 2018). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000119576	SCV005413363	likely pathogenic	not provided	2024-01-30	criteria provided, single submitter	clinical testing	PP3, PM1, PS3_supporting, PS4_moderate
All of Us Research Program, National Institutes of Health	RCV000148805	SCV005430501	likely pathogenic	Malignant hyperthermia, susceptibility to, 1	2024-09-25	criteria provided, single submitter	clinical testing	The c.1589G>A (p.Arg530His) variant, located on the exon 15 of the RYR1 gene, replaces arginine with histidine at codon 530. This missense change has been observed in five unrelated individuals with personal or family histories of a malignant hyperthermia reaction, positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) (PMID:19191329, 19191333, 30236257, 35718563). This variant has been reported to segregate with malignant hyperthermia susceptibility (MHS) in two individuals (PMID:19191333). This variant is located in a mutational hot spot that has been reported to contribute to MHS (PMID: 21118704). Although a functional study found that B-lymphocytes expressing RYR1 variant p.Arg530His displayed higher activity compared with controls, accounting for the MH-susceptible phenotype, this assay is not considered a standard assay by the ClinGen RYR1 Variant Curation Expert Panel for MHS (PMID:27646467). Computational prediction (REVEL >0.85) suggests that this variant may have deleterious impact on protein structure and function. This variant has been classified as likely pathogenic/pathogenic by multiple submitters in ClinVar including the expert review panel (ID: 133101). This variant is rare (14/251494 chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Therefore, the c.1589G>A(p.Arg530His) variant in the RYR1 gene is classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005016407	SCV005647454	likely pathogenic	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; King Denborough syndrome	2024-05-21	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000148805	SCV005871513	likely pathogenic	Malignant hyperthermia, susceptibility to, 1		criteria provided, single submitter	clinical testing	PS4_Moderate+PM1+PP3_Moderate
Color Diagnostics, LLC DBA Color Health	RCV000148805	SCV006064067	likely pathogenic	Malignant hyperthermia, susceptibility to, 1	2025-01-21	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 530 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. This variant occurs in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). It has been shown that immortalized B-lymphocytes from individuals carrying this variant undergo higher acidification after treatment with 4-CmC or ryanodine than B-lymphocytes carrying wild-type RYR1 (PMID: 19191333, 27646467). This variant has been reported in seven families/individuals affected with malignant hyperthermia susceptibility (PMID: 19191329, 19191333, 27646467, 30236257, 33625594, 35718563), including four families/individuals with a personal or family history of a malignant hyperthermia event and a positive in vitro contracture test (PMID: 19191329, 30236257, 35718563) and one individual who carried another pathogenic variant in the RYR1 gene (PMID: 33625594). This variant has been observed in three related individuals affected with malignant hyperthermia susceptibility (PMID: 19191333). This variant has been identified in 14/251494 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
RYR1 database	RCV000119576	SCV000154483	not provided	not provided		no assertion provided	not provided
CSER _CC_NCGL, University of Washington	RCV000148805	SCV000190543	pathogenic	Malignant hyperthermia, susceptibility to, 1	2014-06-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV000655554	SCV000852482	likely pathogenic	RYR1-related disorder	2024-08-06	no assertion criteria provided	clinical testing	The RYR1 c.1589G>A variant is predicted to result in the amino acid substitution p.Arg530His. This variant has been reported to be causative for malignant hyperthermia (MH) in two unrelated families, with functional evidence supporting pathogenicity (Zullo et al. 2009. PubMed ID: 19191333; Robinson et al. 2006. PubMed ID: 16917943). At PreventionGenetics we have observed this variant in the compound heterozygous state in two patients with congenital myopathy. This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD. We classify this variant as likely pathogenic for both dominant and recessive RYR1-related disorders.