Submissions for variant NM_000540.3(RYR1):c.10616G>A (p.Arg3539His)

gnomAD frequency: 0.00171  dbSNP: rs143987857

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV001802859	SCV002047661	likely benign	Malignant hyperthermia of anesthesia	2021-11-10	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 3539 of the RYR1 protein, p.(Arg3539His). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.00305, this is considered to be more common than expected for a pathogenic variant causing autosomal dominantly inherited MHS, BS1. This variant has been reported in 10 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) (PMID:30236257; PMID:23460944; PMID:23558838; PMID:24433488; PMID:25960145), however, the high MAF in the NFE population precludes the use of PS4. This variant has been identified in multiple individuals with negative IVCT/CHCT results, BS2 (PMID:18253926, PMID:22473935). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.877) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID: 29300386). Criteria implemented: PP3_Moderate, BS1, BS2.
Eurofins Ntd Llc (ga)	RCV000119414	SCV000232393	uncertain significance	not provided	2016-08-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000119414	SCV000234974	likely benign	not provided	2021-08-16	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000203202	SCV000257708	uncertain significance	not specified	2015-06-18	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000209955	SCV000265737	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2013-07-01	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000203202	SCV000540251	uncertain significance	not specified	2017-01-24	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is classified in HGMD as DM relating to central core disease and is reported in 10 papers, with comments suggesting VUS/LB. This variant has a Max MAF of 0.30% in ExAC (384/126200 European chrs including 1 homozygote - high for central core disease prevalence of 6/100,000). It is classified in ClinVar as VUS by 4 submitters (Emory, GeneDx, CHOP, Biesecker), and Likely benign by U Wash.
CeGaT Center for Human Genetics Tuebingen	RCV000119414	SCV000575180	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	RYR1: BS1
Genetic Services Laboratory, University of Chicago	RCV000203202	SCV000596887	uncertain significance	not specified	2017-02-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001085699	SCV000659754	likely benign	RYR1-related disorder	2024-01-29	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000119414	SCV000852216	uncertain significance	not provided	2016-05-25	criteria provided, single submitter	clinical testing
Mendelics	RCV000209955	SCV001141071	benign	Malignant hyperthermia, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000119414	SCV001474664	uncertain significance	not provided	2021-06-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000203202	SCV002074555	likely benign	not specified	2022-01-07	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000119414	SCV002541636	uncertain significance	not provided	2021-06-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000119414	SCV003820576	uncertain significance	not provided	2023-09-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000209955	SCV004358187	likely benign	Malignant hyperthermia, susceptibility to, 1	2022-08-18	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000119414	SCV004563935	likely benign	not provided	2023-11-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000119414	SCV005207182	likely benign	not provided		criteria provided, single submitter	not provided
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786375	SCV005398102	uncertain significance	RYR1-related myopathy	2020-05-21	criteria provided, single submitter	clinical testing	A heterozygous missense variant was identified, NM_000540.2(RYR1):c.10616G>A in exon 71 of 106 of the RYR1 gene. This substitution is predicted to create a minor amino acid change from arginine to histidine at position 3539 of the protein, NP_000531.2(RYR1):p.(Arg3539His). The arginine at this position has very high conservation (100 vertebrates, UCSC), but is not situated in a known functional domain (PDB, NCBI). In silico software predicts this variant to be damaging (PolyPhen, SIFT, CADD, MutationTaster). The variant is present in the gnomAD population database at a global allele frequency of 0.164% (462 heterozygotes; 1 homozygote), and is enriched in the European (non-Finnish) population at a frequency of 0.3%. An alternative change to cysteine at the same residue has also been reported in the gnomAD database at a frequency of 0.0008%. Previous reports of the pathogenicity of this variant are conflicting (ClinVar, Monnier, N. et al. (2008), Voermans, N. et al. (2013), Snoeck, M. et al. (2015), Knuiman, G. et al. (2019)). Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS).
Leiden Muscular Dystrophy (RYR1)	RCV000119414	SCV000154321	not provided	not provided		no assertion provided	not provided
CSER _CC_NCGL, University of Washington	RCV000148796	SCV000190534	likely benign	Central core myopathy	2014-06-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000119414	SCV001552609	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000119414	SCV001744337	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000119414	SCV001806817	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000119414	SCV001953585	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000119414	SCV001980081	uncertain significance	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000119414	SCV002037066	uncertain significance	not provided		no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV001085699	SCV002075091	not provided	RYR1-related disorder		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 05-17-2017 by Lab or GTR ID 303161. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.