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 leucine with proline at codon 4665 of the RYR1 protein, p.(Leu4665Pro), c.13994_13995delTCinsCT. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported as de novo in one individual with a personal history of a malignant hyperthermia reaction. This individual did not have a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (PMID: 17483490), PS4 was not met, PM6_supporting was implemented. 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_Sup (PMID: 21118704). No REVEL score was available for this variant. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM6_Supporting, PM1_Supporting.