Submissions for variant NM_000540.3(RYR1):c.9848G>A (p.Arg3283Gln)

gnomAD frequency: 0.00001  dbSNP: rs757753317

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV001803394	SCV002047649	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 arginine with glutamine at codon 3283 of the RYR1 protein, p.(Arg3283Gln). The maximum allele frequency for this variant among the six major gnomAD populations is AMR: 0.000087, 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 without a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result, PS4 not implemented (PMID:23558838). 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 of 0.527 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. No criteria implemented.
GeneDx	RCV001757831	SCV001987767	uncertain significance	not provided	2020-09-14	criteria provided, single submitter	clinical testing	Previously observed in an individual who reportedly died due to MH; however, this patient also harbored a variant in the CACNA1S gene (Brandom et al., 2013); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23558838)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001882824	SCV002210134	uncertain significance	RYR1-related disorder	2022-08-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 3283 of the RYR1 protein (p.Arg3283Gln). This variant is present in population databases (rs757753317, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1303276). 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 not expected to disrupt RYR1 protein function. 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.
All of Us Research Program, National Institutes of Health	RCV004008983	SCV004828025	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-10-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 3283 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual who experienced a fatal malignant hyperthermia event and was also found to carry a variant of uncertain significance in CACNA1S (PMID: 23558838, 25268394). This variant has been identified in 5/249582 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.