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 histidine with glutamine at codon 2204 of the RYR1 protein, p.(His2204Gln). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in six unrelated individuals who have a personal or family history of a malignant hyperthermia reaction; five 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, MH Investigation Unit (MHIU), UHN, Toronto). This variant segregates with MHS in two meioses PP1 (The UK (Leeds) MH Unit). 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 (PMID: 21118704). A REVEL score of 0.739 supports neither a pathogenic nor a benign status for this variant. This variant was initially reported to segregate with positive IVCT status in five individuals meeting PP1_Moderate and contributing to a classification of Likely Pathogenic. After review it was determined that an IVCT positive/genotype negative individual in one of the families demonstrating segregation removed that family from consideration (3 meioses) for PP1. The remaining two meisoses would not meet PP1 based on RYR1 specified ACMG rules for variant interpretation. However, the RYR1-MHS VCEP has decided to leave the variant classification at Likely Pathogenic. It it should be noted that this is based on expert opinion and not a strict adherence to the RYR1 specified ACMG rules for variant interpretation. Criteria implemented: PS4_Moderate, PM1, PP1.