Submissions for variant NM_000540.3(RYR1):c.6961A>G (p.Ile2321Val)

gnomAD frequency: 0.00058  dbSNP: rs34390345

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV000148810	SCV001816146	benign	Malignant hyperthermia, susceptibility to, 1	2021-03-18	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 isoleucine with valine at codon 2321 of the RYR1 protein p.(Ile2321Val). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.00081, this is considered to be more common than expected for a pathogenic variant causing autosomal dominant MHS, BS1. This variant has been reported in four 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 (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted) (PMID:30236257; PMID:23558838). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. This variant has been identified in families with genotype positive/ phenotype negative individuals (IVCT) supporting a benign status, BS2 (PMID:30236257, personal communications). Variant did not show increased sensitivity to RYR1 agonists in HEK293 assay (personal communication), BS3_Supporting. 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 0.712 does not support pathogenic or a benign status. This variant has been classified as Benign. Criteria implemented: BS1, BS2, BS3_Supporting, PM1.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000148810	SCV000265720	likely benign	Malignant hyperthermia, susceptibility to, 1	2013-07-01	criteria provided, single submitter	research
Illumina Laboratory Services, Illumina	RCV000264566	SCV000412386	likely benign	Neuromuscular disease, congenital, with uniform type 1 fiber	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000329021	SCV000412387	likely benign	Central core myopathy	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000148810	SCV000412388	likely benign	Malignant hyperthermia, susceptibility to, 1	2017-04-27	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000270704	SCV000412389	likely benign	Congenital multicore myopathy with external ophthalmoplegia	2017-04-27	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000454582	SCV000540248	uncertain significance	not specified	2017-02-03	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 present in HGMD in 5 papers but classified as VUS. Comments: Variant found in 1/870 ClinSeq participants not selected for malignant hyperthermia susceptibility (24195946); Co-occurred with another variant in RYR1 in a family with MHS (19191329). It is classified in ClinVar with 1 star as Likelybenign by Biesecker and VUS by CSER. It has a max MAF in ExAC of 0.06% (41 alleles) and in gnomAD of 0.08% (101 alleles). Frequency too high for disease - MHS prevalence is estimated at max 1/5000.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000542059	SCV000660009	likely benign	RYR1-related disorder	2024-01-25	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000119672	SCV000852735	uncertain significance	not provided	2017-12-12	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000119672	SCV001151859	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	RYR1: BS1
GeneDx	RCV000119672	SCV001793229	uncertain significance	not provided	2024-06-10	criteria provided, single submitter	clinical testing	Identified in patients with malignant hyperthermia; however, additional clinical information was not provided and functional characterization of the variant was not completed (PMID: 16917943, 30236257); Also reported as a polymorphism (PMID: 19191329, 23558838, 24195946); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24948473, 26972305, 24195946, 26332594, 23558838, 27377473, 20301325, 24055113, 25637381, 30788618, 30236257, 27663056, 34348614, 36208971, 37937776, 12668474, 33767344, 19191329, 16917943)
Fulgent Genetics, Fulgent Genetics	RCV002498552	SCV002811208	benign	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome	2021-10-10	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000119672	SCV003815022	uncertain significance	not provided	2023-08-09	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000148810	SCV004358112	likely benign	Malignant hyperthermia, susceptibility to, 1	2022-07-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000454582	SCV005204401	likely benign	not specified	2024-06-12	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.6961A>G (p.Ile2321Val) results in a conservative amino acid change located in the RIH domain (IPR000699) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00044 in 251396 control chromosomes. The observed variant frequency is approximately 5-fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR1 causing Malignant Hyperthermia Susceptibility phenotype (8.8e-05). c.6961A>G has been reported in the literature in individuals affected with Malignant Hyperthermia Susceptibility without strong evidence for causality (such as segregation) (examples: Brandom_2013, Miller_2018, Levano_2009, Lopez_2016, Jensson_2023). The variant has also been reported to co-occur with other pathogenic variants (RYR1: c.14545G>A, c.38T>G) (Levano_2009, Lopez_2016.). At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (White_2022). The following publications have been ascertained in the context of this evaluation (PMID: 30236257, 37937776, 19191329, 27382027, 36208971, 23558838). ClinVar contains an entry for this variant (Variation ID: 133173). Based on the evidence outlined above, the variant was classified as likely benign.
Leiden Muscular Dystrophy (RYR1)	RCV000119672	SCV000154579	not provided	not provided		no assertion provided	not provided
CSER _CC_NCGL, University of Washington	RCV000148810	SCV000190549	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2014-06-01	no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000119672	SCV001959133	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000119672	SCV001972088	uncertain significance	not provided		no assertion criteria provided	clinical testing