Submissions for variant NM_000540.3(RYR1):c.4178A>G (p.Lys1393Arg)

gnomAD frequency: 0.00282  dbSNP: rs137933390

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV000294059	SCV002047658	benign	Malignant hyperthermia of anesthesia	2022-01-03	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 lysine with arginine at codon 1393 of the RYR1 protein, p.(Lys1393Arg). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0046, which is considered to be too common for a pathogenic variant causing autosomal dominantly inherited MHS, BA1. This variant has been classified as Benign. Criteria implemented: BA1.
Eurofins Ntd Llc (ga)	RCV000487936	SCV000111015	uncertain significance	not provided	2015-06-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000487936	SCV000234967	likely benign	not provided	2020-10-06	criteria provided, single submitter	clinical testing	Reported previously in individuals with features of RYR1-related disorders, but familial segregation information was not always included and some individuals were noted to have other potentially causative variants (Vukcevic et al., 2010; Dlamini et al., 2013; Loseth et al., 2013; Gillies et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26332594, 20142353, 27153395, 25637381, 25985138, 23329375, 24195946, 25735680, 23628358, 28496993, 30788618, 30916033)
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000148803	SCV000265704	benign	Malignant hyperthermia, susceptibility to, 1	2013-07-01	criteria provided, single submitter	research
Illumina Laboratory Services, Illumina	RCV000315938	SCV000412121	likely benign	Neuromuscular disease, congenital, with uniform type 1 fiber	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000372946	SCV000412122	likely benign	Congenital multicore myopathy with external ophthalmoplegia	2018-02-09	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000294059	SCV000412123	likely benign	Malignant hyperthermia of anesthesia	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000348954	SCV000412124	likely benign	Central core myopathy	2018-02-09	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV000487936	SCV000575166	likely benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	RYR1: BS2
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000487936	SCV000609980	uncertain significance	not provided	2017-02-22	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000259079	SCV000614910	uncertain significance	not specified	2017-04-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082546	SCV000659934	likely benign	RYR1-related disorder	2024-02-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000148803	SCV001141059	benign	Malignant hyperthermia, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000487936	SCV001715270	uncertain significance	not provided	2021-12-01	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV000148803	SCV002503612	likely benign	Malignant hyperthermia, susceptibility to, 1	2023-03-30	criteria provided, single submitter	clinical testing	This sequence change is predicted to replace lysine with arginine at codon 1393 of the RYR1 protein (p.(Lys1393Arg)). The lysine residue is conserved (100 vertebrates, UCSC), and there is a small physicochemical difference between lysine and arginine. It is not in an annotated domain. The variant is present in a large population cohort at a frequency of 0.46% in the European non-Finnish population (rs137933390, gnomAD v2.1.1 and v3.0). In comparison, the variant was present at a frequency of 0.46% in a cohort of individuals with malignant hyperthermia susceptibility (PMID: 24195946). This variant has been seen in at least 13 individuals with malignant hyperthermia susceptibility, including some individuals where another RYR1 variant was identified (PMID: 24195946, 19346234, 25960145, 23558838, 24433488, 25735680, 28326467), as well as being present in individuals with myopathy, rhabdomyolysis and exertional heat stroke (PMID: 22473935, 23628358, 23329375, 26565425, 28496993), although several authors acknowledge the high population frequency and comment that the variant is unlikely to be pathogenic. This variant has been shown not to segregate with the malignant hyperthermia susceptibility phenotype in two unrelated families, although the pedigrees have not been confirmed (PMID: 25658027). It has been reported in at least three further individuals without malignant hyperthermia (PMID: 25614869). Functional data from a lymphoblastoid cell line demonstrated 4-chloro-m-cresol induced calcium release at a lower concentration, however it is unclear whether this is a true reflection of the skeletal myocyte (PMID: 20142353). Multiple lines of computational evidence have conflicting predictions for the missense substitution (4/6 algorithms predict benign/neutral effect, 1/6 algorithms predict deleterious effect, 1/6 algorithms have an unknown prediction). Based on the classification guidelines RMH Modified ACMG Guidelines v1.3.0, this variant is classified as LIKELY BENIGN. The following criteria are met: BS1, BP5.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000487936	SCV003799195	uncertain significance	not provided	2022-04-01	criteria provided, single submitter	clinical testing	The RYR1 c.4178A>G, p.Lys1393Arg variant (rs137933390) has been identified in several individuals with clinical suspicion for malignant hyperthermia susceptibility (MHS) syndrome or other related myopathy (Bick 2017, Gillies 2015, Loseth 2013, Vukcevic 2010). Additionally, a cell line isolated from an MHS patient showed increased sensitivity to 4-chloro-m-cresol (Vukcevic 2010). However, variant has been identified at high allele frequency in several control populations, and is found in the non-Finnish European population with an allele frequency of 0.46% (537/ 115776 alleles, including 2 homozygotes) in the Genome Aggregation Database. Due to this high population frequency, the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel considers this variant benign with respect to autosomal dominant MHS (ClinVar Variation ID: 93269). However, this population frequency alone is not high enough alone to rule out a potential role with respect to the recessive myopathies associated with loss of function variation in RYR1. Therefore, while considered benign for MHS specifically, the overall classification of this variant is uncertain. References: Bick D et al. Successful Application of Whole Genome Sequencing in a Medical Genetics Clinic. J Pediatr Genet. 2017 Jun;6(2):61-76. PMID: 28496993 Gillies RL et al. Analysis of the entire ryanodine receptor type 1 and alpha 1 subunit of the dihydropyridine receptor (CACNA1S) coding regions for variants associated with malignant hyperthermia in Australian families. Anaesth Intensive Care. 2015 Mar;43(2):157-66. PMID: 25735680. Loseth S et al. A novel late-onset axial myopathy associated with mutations in the skeletal muscle ryanodine receptor (RYR1) gene. J Neurol. 2013 Jun;260(6):1504-10. PMID: 23329375. Vukcevic M et al. Functional properties of RYR1 mutations identified in Swedish patients with malignant hyperthermia and central core disease. Anesth Analg. 2010 Jul;111(1):185-90. PMID: 20142353.
Color Diagnostics, LLC DBA Color Health	RCV000148803	SCV004358069	likely benign	Malignant hyperthermia, susceptibility to, 1	2022-07-12	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000487936	SCV005207126	likely benign	not provided		criteria provided, single submitter	not provided
CSER _CC_NCGL, University of Washington	RCV000148803	SCV000190541	likely benign	Malignant hyperthermia, susceptibility to, 1	2014-06-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV001082546	SCV000852606	likely benign	RYR1-related disorder	2024-07-25	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000487936	SCV001744544	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000259079	SCV001932410	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000487936	SCV001953302	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000487936	SCV002036318	likely benign	not provided		no assertion criteria provided	clinical testing