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 cysteine with arginine at codon 35 of the RYR1 protein, p.(Cys35Arg). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000009, a frequency consistent with pathogenicity for MHS. This variant has been reported in three unrelated individuals who have a personal or family history of a malignant hyperthermia reaction and 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:17710899, PMID:20681998, PMID:9066328). Functional studies in HEK293 cells show conflicting data regarding sensitivity to RYR1 agonists, PS3/BS3 were not implemented (PMID:9334205, 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). This variant segregates with MHS in 11 individuals, PP1_Strong (PMID:9066328). A REVEL score > 0.85 supports pathogenicity, PP3_Moderate. Criteria implemented: PS4_Moderate, PM1, PP3_Moderate, PP1_Strong. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386).