CPIC Guideline for Potent Volatile Anesthetic Agents and Succinylcholine - RYR1 variant update

The original guideline, supplement, and the supporting gene and drug files are available on the CPIC website. Annotations of the guideline, including an interactive genotype picker tool are available on the PharmGKB website.

Subsequent to the publication of the CPIC Guideline for the Use of Potent Volatile Anesthetic Agents and Succinylcholine in the Context of RYR1 or CACNA1S Genotypes (PMID 30499100), the ClinGen malignant hyperthermia susceptibility (MHS) variant curation expert panel (VCEP) developed and published recommendations for RYR1 pathogenicity classifications in malignant hyperthermia susceptibility (PMID 35849058). CPIC has added an additional 291 variants and updated the RYR1 allele definition, frequency, and functionality tables accordingly (additional details can be found in the notes tab of the RYR1 allele functionality table). 

Pathogenic and likely pathogenic variants are assigned a CPIC function of Malignant Hyperthermia associated, variants of uncertain significance (VUS) are mapped to uncertain function, and benign and likely benign variants are assigned normal function. 

Additionally, CPIC has created a RYR1 diplotype to phenotype table. RYR1 phenotypes are determined based on the function combinations of two RYR1 variants. The RYR1 diplotype to phenotype table contains all possible combinations of two RYR1 variants included in the RYR1 allele functionality file. In case >2 variants are found, the variants with Malignant Hyperthermia associated function should be used first. If 2 Malignant Hyperthermia associated variants are found, those are assumed on different chromosomes.