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 histidine at codon 401 of the RYR1 protein, p.(Arg401His). The maximum allele frequency for this variant in the Finish population in gnomAD was 0.000046 with one alternate allele. This variant was not identified in any of the six continental populations in gnomAD. This is consistent with pathogenicity. This variant has been reported in eight unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, eight 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 (PMID:12059893, PMID:16163667, PMID:30236257, PMID:23460944, PMID:24433488). This variant segregates with MHS in three individuals, PP1_Supporting ( PMID:12059893). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists PS3_Moderate (PMID:26115329, PMID:31841587). 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 three individuals, PP1_Supporting (PMID:12059893). A REVEL score >0.85 (0.903) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS3_Moderate, PS4, PM1, PP1_Supporting, PP3_Moderate.