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 asparagine with serine at codon 2342 of the RYR1 protein p.(Asn2342Ser). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.00206, which is considered to be more common than expected for a pathogenic variant causing autosomal dominantly inherited MHS, BS1. This variant has been reported in over ten unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, at least nine of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted)( PMID:30236257, PMID:23558838, PMID:24433488, personal communication) However, the high MAF in the NFE population in gnomAD precludes the use of PS4. This variant has been shown to segregate with IVCT status in at least three individuals across two families, PP1 (PMID:30236257, personal communication). In other families at least two genotype positive IVCT negative individuals have been reported, BS2 (PMID:15221887, personal communication). HEK293 assay shows increased sensitivity to 4CmC, PS3_Moderate (PMID: 15221887). A functional study published using B-lymphocytes showed increased acidification rates, however, this assay is not considered a standard assay by the ClinGen RYR1 VCEP for MHS (PMID:19191333). 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 0.639 supports neither a pathogenic or a benign status. Criteria implemented include: PS3_Moderate, PM1, PP1, BS1, BS2. Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID: 29300386).