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 lysine with glutamic acid at codon 33 of the RYR1 protein, p.(Lys33Glu). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual diagnosed with King-Denborough syndrome with a personal history of an MH episode and a positive caffeine halothane contracture test (CHCT) result, PS4_Supporting (PMID:18765655). In this individual the variant was determined to be de novo without confirmed parentage PM6_Supporting. 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 >0.85 (0.92) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Likely Pathogenic: PM6_Supporting, PS4_Supporting, PM1, PP3_Moderate.