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 tryptophan at codon 2359 of the RYR1 protein, p.(Arg2359Trp). The maximum allele frequency for this variant among the six major gnomAD populations is AMR: 0.00003, a frequency consistent with pathogenicity for MHS. This variant has been reported in a mutation report without clinical details and this does not satisfy PS4 (PMID:16521288). No functional studies were identified for this variant. Another variant assessed as likely pathogenic occurs at this codon, p.(Arg2359Gln), PM5_Supporting. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PM5 (PMID: 21118704). A REVEL score >0.85 (0.93) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1_Supporting, PM5_Supporting, PP3_Moderate.