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 serine with tyrosine at codon 71 of the RYR1 protein, p.(Ser71Tyr). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in the literature in individuals with autosomal recessive myopathies. It has also been described in individuals that were noted to be MHS but without a clear history of an MH reaction. These cases did not meet the criteria for PS4 according to the ClinGen RYR1 VCEP for MHS, (PMID:16835904, PMID:16940308, PMID:17365175). Functional studies published for this variant test the variant in trans with other variants and these studies were not considered for PS3/BS3, (PMID:16940308). 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 >0.85 (0.937) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: PM1, PP3_Moderate.