Submissions for variant NM_000540.3(RYR1):c.6302T>A (p.Met2101Lys)

gnomAD frequency: 0.00006  dbSNP: rs746818096

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV001592839	SCV001815861	uncertain significance	Malignant hyperthermia of anesthesia	2023-04-06	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 methionine with lysine at codon 2101 of the RYR1 protein, p.(Met2101Lys). The maximum minor allele frequency (MAF) for this variant among the six major gnomAD populations is NFE: 0.000087, a frequency consistent with pathogenicity for MHS. However, the MAF in the Ashkenazi Jewish population is 0.0047 which is considered to be too common for a pathogenic variant causing autosomal dominantly inherited MHS. This variant has been reported in three 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). One of these individuals had a second variant of uncertain significance in RYR1 (p.Arg1469Trp, VUS) (PMID:20681998, PMID:25735680, PMID:30236257). The high MAF in the Ashkenazi Jewish population precludes implementing PS4. No functional studies were identified for this variant. 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 <0.5 (0.392) supports a benign status for this variant, BP4. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1, BP4.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001087847	SCV000777634	likely benign	RYR1-related disorder	2024-10-30	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000721605	SCV000852702	uncertain significance	not provided	2015-12-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001127338	SCV001286640	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2017-04-28	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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001127339	SCV001286641	uncertain significance	Congenital multicore myopathy with external ophthalmoplegia	2017-04-28	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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV000721605	SCV002546774	uncertain significance	not provided	2024-06-20	criteria provided, single submitter	clinical testing	Identified in individuals with malignant hyperthermia in published literature, although these patients either harbored other RYR1 variants or functional characterization of the variant was not completed (PMID: 25735680, 12709367, 30236257); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 37937776, 12709367, 20681998, 25735680, 12668474, 30236257)
Revvity Omics, Revvity	RCV000721605	SCV003827500	uncertain significance	not provided	2022-05-11	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000721605	SCV004141600	uncertain significance	not provided	2023-01-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488776	SCV004241842	uncertain significance	not specified	2023-12-05	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.6302T>A (p.Met2101Lys) results in a non-conservative amino acid change located in the Ryanodine receptor, junctional solenoid domain (IPR048581) 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 0.00024 in 247564 control chromosomes (gnomAD). c.6302T>A has been reported in the literature in individuals affected with malignant hyperthermia susceptibility (examples: Tammaro_2003, Tammaro_2011, Gillies_2015, Miller_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Myopathy, RYR1-Associated. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25735680, 30236257, 12709367, 20681998). Seven submitters including ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=6, includes the expert panel) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.