Submissions for variant NM_000540.3(RYR1):c.526G>A (p.Glu176Lys)

gnomAD frequency: 0.00001  dbSNP: rs761616815

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV003221838	SCV002570142	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 glutamic acid with lysine at codon 176 of the RYR1 protein, p.(Glu176Lys). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.0000649, a frequency consistent with pathogenicity for MHS. This variant has been reported in three individuals with a personal or family history of an MH episode and 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:30236257, MH Investigation Unit (MHIU), UHN, Toronto). 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 of 0.803 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS4_Moderate, PM1.
Eurofins Ntd Llc (ga)	RCV000721583	SCV000231553	uncertain significance	not provided	2014-11-17	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000179321	SCV000596893	uncertain significance	not specified	2017-02-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000549945	SCV000659958	uncertain significance	RYR1-related disorder	2024-04-04	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 176 of the RYR1 protein (p.Glu176Lys). This variant is present in population databases (rs761616815, gnomAD 0.007%). This missense change has been observed in individual(s) with autosomal dominant malignant hyperthermia susceptibility (Invitae). ClinVar contains an entry for this variant (Variation ID: 198090). 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%. This variant disrupts the p.Glu176 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been observed in individuals with RYR1-related conditions (PMID: 29635721; Invitae), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV000765443	SCV000896734	uncertain significance	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion	2018-10-31	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000721583	SCV003814973	uncertain significance	not provided	2021-10-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996579	SCV004820715	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 176 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). This variant occurs in a region of the RYR1 protein that is considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least four individuals affected with malignant hyperthermia susceptibility (PMID: 30236257; ClinVar: SCV002570142.2, SCV000659958.3) and in four individuals affected with heat sensitivity, heat-induced rhabdomyolysis, or exertional rhabdomyolysis (PMID: 28326467, 33037202). This variant has been identified in 8/251062 chromosomes 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.
PreventionGenetics, part of Exact Sciences	RCV000549945	SCV000852676	uncertain significance	RYR1-related disorder	2024-07-30	no assertion criteria provided	clinical testing	The RYR1 c.526G>A variant is predicted to result in the amino acid substitution p.Glu176Lys. This variant was reported in the literature in one family with malignant hyperthermia (Miller et al., 2018. PubMed ID: 30236257). This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD. This variant has been classified as a variant of uncertain significance by multiple submitters in clinvar including the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/198090/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.