Most recent guideline publication:
Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for the use of potent volatile anesthetic agents and succinylcholine in the context of RYR1 or CACNA1S genotypes
Updates since publication:
December 2023: Subsequent to the publication of the CPIC guideline for RYR1 and malignant hyperthermia (PMID 30499100), the ClinGen 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 allele definition table, frequency, and functionality tables accordingly (additional details can be found in the notes tab of the RYR1 allele functionality table). Additionally, CPIC has created RYR1 and CACNA1S diplotype to phenotype tables. See the notes tab in the supporting files and this blogpost for mappings from pathogenicity terms to CPIC terms and details of diplotypes in the case of >2 RYR1 variants found.
July 2023: As part of the Malignant Hyperthermia Susceptibility VCEP two-year variant review. c.1589G>A (R530H) is now classified as Likely Pathogenic and c.14582G>A (R4861H) is now classified as VUS. Based on this classification, the assignment for the variant c.1589G>A has been changed from “uncertain function” to “malignant hyperthermia-associated” and for the variant c.14582G>A from “malignant hyperthermia-associated” to “uncertain function” in the RYR1 allele functionality table. Additional variants beyond these 44 have been identified by the VCEP and the current CPIC authors are reviewing these variants for inclusion in the CPIC tables.
November 2021: Subsequent to the publication of the CPIC guideline for RYR1 and malignant hyperthermia (PMID 30499100), the ClinGen variant curation expert panel (VCEP) developed and published recommendations for RYR1 pathogenicity classifications in malignant hyperthermia susceptibility. These revised ACMG/AMP criteria were applied to the 44 variants originally included in the CPIC recommendations and 29 variants were classified as pathogenic, 13 as likely pathogenic, and 2 as variants of uncertain significance (PMID 33767344). Based on this classification, the assignment for the variants c.1589G>A p.(Arg530His) and c.1598G>A p.(Arg533His) has been changed from “malignant hyperthermia-associated” to “uncertain function” in the RYR1 allele functionality table. Additional variants beyond these 44 have been identified by the VCEP and the current CPIC authors are reviewing these variants for inclusion in the CPIC tables.
September 2019: The published version of this article included a typographical error in Table 1 and in the supplemental tables: RYR1 c.488G>A should instead be listed as RYR1 c.488G>T. The Table 1 in guideline, RYR1 allele definition table, RYR1 allele functionality table, and RYR1 frequency table have been updated accordingly.
Tables provided in the main manuscript of the guideline:
| Table 1. Assignment of RYR1 and CACNA1S phenotype based on genotype |
| Table 2. Recommended therapeutic use of inhaled anesthetics and succinylcholine in relation to RYR1 and CACNA1S phenotype |
Supplement to: Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for the use of potent volatile anesthetic agents and succinylcholine in the context of RYR1 or CACNA1S genotypes
Tables and figures included in the supplement or referenced in the guidelinea:
| Supplemental Table S1. Evidence linking RYR1 and CACNA1S genotype with malignant hyperthermia |
| RYR1 allele definition table |
| RYR1 allele functionality table |
| RYR1 frequency table |
| RYR1 diplotype to phenotype table |
| CACNA1S allele definition table |
| CACNA1S allele functionality table |
| CACNA1S frequency table |
| CACNA1S diplotype to phenotype table |
| Gene resource mapping RYR1 gene resource mappings |
| Drug resource mapping DesfluraneEnflurane Halothane Isoflurane Methoxyflurane Sevoflurane Succinylcholine |
Clinical decision support:b Implementation workflowRYR1 consult text CACNA1S consult text Succinylcholine pre-test and post-test alerts Desflurane pre-test and post-test alerts Enflurane pre-test and post-test alerts Halothane pre-test and post-test alerts Isoflurane pre-test and post-test alerts Methoxyflurane pre-test and post-test alerts Sevoflurane pre-test and post-test alerts |
aSome of the tables included in the guideline may have been updated online, particularly to reflect newly described or newly characterized alleles. These include the gene-specific information tables (https://www.pharmgkb.org/page/pgxGeneRef) that support CPIC guidelines by providing information regarding star (*) allele definitions, allele function, allele frequency by major ethnic groups, translations of diplotype to phenotype, and gene resource mappings.
bThese resources support the adoption of CPIC guidelines into the electronic health record with clinical decision support and provide information that clinical implementers find helpful.