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 threonine with arginine at codon 2206 of the RYR1 protein, p.(Thr2206Arg). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in four unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, two 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: 10484775, 30236257, 16244001). This variant segregates with MHS in six individuals, PP1_Moderate (PMID: 10484775). A functional study in HEK293 cells shows an increased sensitivity to RYR1 agonists PS3_Moderate (PMID: 16163667). 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 (0.968) supports a pathogenic status for this variant, PP3_Moderate. 75e1f85c-b5bd-4e59-83c6-5d22ed39b50e 75e1f85c-b5bd-4e59-83c6-5d22ed39b50e RYR1 NC_000019.10 g.38543551A>G NM_000540.2(RYR1):c.11798A>G|p.Tyr3933Cys MONDO MONDO:0007783 Likely Benign 2022-01-04 assertion-criteria Autosomal dominant inheritance https://erepo.clinicalgenome.org/evrepo/ui/interpretation/75e1f85c-b5bd-4e59-83c6-5d22ed39b50e 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 tyrosine with cysteine at codon 3933 of the RYR1 protein, p.(Tyr3933Cys). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.001332, 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 six unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all 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: 25958340, 20681998, 23558838, 25658027, 25735680). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.983) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is classified as Pathogenic, (PMID: 29300386). Criteria implemented: PS3_Moderate, PS4_Moderate, PM1, PP1_Moderate, PP3_Moderate.