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 1679 of the RYR1 protein, p.(Arg1679His). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0022, 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 2 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 2 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:19346234, PMID:20142353). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. This variant has been identified in an individual with negative IVCT/CHCT result, BS2_Moderate (PMID:19346234). A functional study was published for this variant using patient lymphocytes, this assay is not considered a standard assay by the ClinGen RYR1 VCEP for MHS (PMID:20142353). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.918) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID: 29300386). Criteria implemented: BS1, BS2_Moderate, PP3_Moderate.