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 threonine with methionine at codon 214 of the RYR1 protein, p.(Thr214Met). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.00017, a frequency consistent with pathogenicity for MHS. This variant has been reported in four 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 (PMID:30236257). This variant has been reported in a fifth individual with a second variant in RYR1 classified as Likely Pathogenic (p.Glu2348del), this individual was not counted toward PS4 (PMID:27857962), the mother of this individual shared the p.Thr214Met variant and was MHN by IVCT, BS2_Moderate. Functional studies in HEK293 cells do not show a significant increase in sensitivity to RYR1 agonists, BS3_Supporting (PMID:27857962). This variant segregates with MHS in three individuals, PP1 (PMID:25658027, PMID:30236257). 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 of 0.533 supports neither a pathogenic nor a benign status for this variant. Based on using Bayes to combine criteria this variant is assessed as a Variant of Uncertain Significance, (PMID: 29300386). Criteria implemented: PS4_Moderate, PM1, PP1, BS2_Moderate, BS3_Supporting.