Submissions for variant NM_000540.3(RYR1):c.7099G>A (p.Ala2367Thr)

gnomAD frequency: 0.00003  dbSNP: rs146306934

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV000148823	SCV002047603	uncertain significance	Malignant hyperthermia, susceptibility to, 1	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 alanine with threonine at codon 2367 of the RYR1 protein, p.(Ala2367Thr). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0000559, a frequency consistent with pathogenicity for MHS. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, both 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:11575529, The UK (Leeds) MH Unit). 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 >0.85 (0.899) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Supporting, PM1, PP3_Moderate.
PreventionGenetics, part of Exact Sciences	RCV000119688	SCV000852752	uncertain significance	not provided	2021-02-22	criteria provided, single submitter	clinical testing
Invitae	RCV001059591	SCV001224218	likely pathogenic	RYR1-related disorder	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2367 of the RYR1 protein (p.Ala2367Thr). This variant is present in population databases (rs146306934, gnomAD 0.01%). This missense change has been observed in individuals with malignant hyperthermia susceptibility (PMID: 11575529; Invitae). ClinVar contains an entry for this variant (Variation ID: 133187). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RYR1 protein function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002483209	SCV002788263	uncertain significance	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome	2022-05-31	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000119688	SCV003813170	uncertain significance	not provided	2022-08-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000148823	SCV004820901	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 2367 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Although functional studies have not been reported for this variant, it occurs in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). This variant has been reported in at least one individual affected with a malignant hyperthermia reaction with a positive caffeine halothane contracture test (CHCT) (PMID: 11575529, 15448513). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Leiden Muscular Dystrophy (RYR1)	RCV000119688	SCV000154595	not provided	not provided		no assertion provided	not provided
CSER _CC_NCGL, University of Washington	RCV000148823	SCV000190562	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2014-06-01	no assertion criteria provided	research