Submissions for variant NM_000540.3(RYR1):c.12398A>G (p.Glu4133Gly)

gnomAD frequency: 0.00006  dbSNP: rs201321695

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV001449980	SCV001653529	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 glycine at codon 4133 of the RYR1 protein, p.(Glu4133Gly). 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 identified in an individual reported to have undergone an MH episode (CGS 10), the individual had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (PMID: 24433488). The MAF in the SAS population in gnomAD is 0.000065, assuming ~3,000 MH cases described in the literature an odds ratio calculation would allow for PS4_Supporting. 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 (0.881) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PP3_Moderate.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000810392	SCV000950589	uncertain significance	RYR1-related disorder	2022-08-30	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 4133 of the RYR1 protein (p.Glu4133Gly). This variant is present in population databases (rs201321695, gnomAD 0.006%). This missense change has been observed in individual(s) with malignant hyperthermia susceptibility (PMID: 24433488). ClinVar contains an entry for this variant (Variation ID: 654427). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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	RCV002495119	SCV002776389	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	2021-10-16	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV003132073	SCV003812498	uncertain significance	not provided	2023-01-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004001723	SCV004816225	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 4133 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual who experienced a malignant hyperthermia event (CGS 10) (PMID: 24433488). This variant has been identified in 10/282520 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.