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 leucine at codon 163 of the RYR1 protein p.(Arg163Leu). This variant is absent from a large population databases (gnomAD). This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, two of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted), PS4_Moderate (PMID:30236257, PMID:16163667). This variant segregates with MHS in five individuals, PP1_Moderate (PMID:35718563). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:16163667, PMID:26115329). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID:21118704). Another variant assessed as pathogenic occurs at this codon, p.(Arg163Cys), however PM5 was not applied as Arg→Cys is predicted to be more disruptive based on a higher Grantham score as compared to Arg→Leu. A REVEL score > 0.85 supports pathogenicity, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID:29300386). Criteria implemented: PS4_Moderate, PS3_Moderate, PM1, PP1_Moderate, PP3_Moderate.