CPIC® Guideline for Potent Volatile Anesthetic Agents and Succinylcholine and RYR1 and CACNA1S

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

CACNA1S gene resource mappings

Drug resource mapping

Desflurane
Enflurane
Halothane
Isoflurane
Methoxyflurane
Sevoflurane
Succinylcholine

Clinical decision support:b

Implementation workflow

RYR1 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.