Submissions for variant NM_000540.3(RYR1):c.251C>T (p.Thr84Met)

gnomAD frequency: 0.00004  dbSNP: rs186983396

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV001580398	SCV001810083	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 threonine with methionine at codon 84 of the RYR1 protein, p.(Thr84Met). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.0003, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual 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), (PMID:30236257), however, the high MAF in the EAS population in gnomAD precludes the use of PS4. Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists PS3_Moderate (PMID:29344738). 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 0.735 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PS3_Moderate, PM1.
Baylor Genetics	RCV001332535	SCV001524892	uncertain significance	Central core myopathy		criteria provided, single submitter	clinical testing
Invitae	RCV001858844	SCV002129395	uncertain significance	RYR1-related disorder	2022-07-19	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 84 of the RYR1 protein (p.Thr84Met). This variant is present in population databases (rs186983396, gnomAD 0.03%). This missense change has been observed in individual(s) with autosomal dominant congenital myopathy (PMID: 29344738). ClinVar contains an entry for this variant (Variation ID: 808527). 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: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects RYR1 function (PMID: 29344738, 33490280). 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	RCV002481781	SCV002782926	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	2021-10-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV001858844	SCV004116789	uncertain significance	RYR1-related disorder	2023-04-20	criteria provided, single submitter	clinical testing	The RYR1 c.251C>T variant is predicted to result in the amino acid substitution p.Thr84Met. This variant has been reported in two siblings with congenital myopathy and a muscle biopsy from one indicated susceptibility to malignant hyperthermia (Kondo et al 2018. PubMed ID: 29344738). However, this variant was also observed in the unaffected mother and brother, indicating this variant is less likely to be causative for a dominant RYR1-related myopathy. This variant is reported in 0.030% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-38933074-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV004004441	SCV004820707	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 84 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). Functional studies have shown that HEK293 cells expressing this variant and carrier-derived myotubes are hypersensitive to caffeine and 4-CmC compared to cells expressing wild-type RYR1 (PMID: 29344738, 33490280). This variant has been reported in at least two individuals affected with malignant hyperthermia susceptibility, one of these individuals was diagnosed by Ca2+-induced Ca2+ release (CICR) rate (PMID: 29344738, 30236257, 35549722). This variant has been identified in 9/282262 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.