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 Alanine with Valine at codon 4295 of the RYR1 protein, p.(Ala4295Val). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0019, this is considered to be more common than expected for a pathogenic variant causing autosomal dominantly inherited MHS, BS1. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, both 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), (PMID:30236257). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. This variant has been identified in an individual with a negative IVCT/CHCT result, BS2_Moderate, (PMID:25658027). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. This variant was observed in cis with a variant assessed as pathogenic, p.(Arg2435His), BP2 (PMID:19513315). A REVEL score <0.5 (0.152) supports a benign status for this variant, BP4. Based on using Bayes to combine criteria this variant is assessed as Benign, (PMID: 29300386). Criteria implemented: BS1, BS2_Moderate, BP2, BP4.