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 valine with 2627 at codon leucine of the RYR1 protein, p.(Val2627Leu). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000065, 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, all of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Moderate (The UK (Leeds) MH Unit). This variant segregates with MHS in seven individuals, PP1_Strong (The UK (Leeds) MH Unit). 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 >0.85 (0.894) supports a pathogenic, PP3_Moderate. This variant has been classified as Likey Pathogenic. Criteria implemented: PS4_Moderate, PP1_Strong, PP3_Moderate.