The Gene2Rx malignant hyperthermia screen

At a glance

Genes

RYR1 and CACNA1S

Sites checked

348 variants from CPIC's allele tables: 98 MH-associated (96 RYR1, 2 CACNA1S); 216 uncertain function (RYR1); 34 normal function (RYR1).

Variant list

The CPIC RYR1 and CACNA1S allele functionality tables [2] [3], as retrieved on September 4, 2026 (definition version cpic-mh-2026-09-04).

Guideline

CPIC guideline for potent volatile anesthetics and succinylcholine in the context of RYR1 or CACNA1S genotypes (2019) [1].

Input

The person's own whole-genome sequencing file (VCF, one sample), on GRCh37 or GRCh38. Consumer genotyping arrays such as 23andMe and AncestryDNA are never screened.

What it is

A targeted lookup of listed variants. Gene2Rx is not a clinical laboratory, and a finding should be confirmed by a clinical genetic test before it guides care.

• MH-associated 98
• Uncertain function 216
• Normal function 34

Why the screen looks for these variants

CPIC's recommendations are written for the variants it classes as MH-associated. Carrying one copy is enough for CPIC to presume a person susceptible and to call the potent volatile anesthetics and succinylcholine relatively contraindicated, a strong recommendation [1]. The screen therefore checks exactly the sites in CPIC's tables and reports CPIC's phenotypes, so a positive result maps directly onto the guideline.

It also looks for the variants CPIC lists as uncertain or normal function. Finding one of those does not change the recommendation, but it does change what the report can honestly say: a person carrying a variant of uncertain function is not told that nothing was found.

The design choices follow from how rare these variants are and what a wrong call would cost:

• No imputation. An MH variant inferred from nearby markers isn't reliable enough to act on, so array data, and VCF files that turn out to be array exports, are not screened.
• The original file. The screen reads the upload as received, in its own genome build, before the rest of the report lifts it over, fills in missing positions or phases it.
• No assumed reference calls. Many VCF files list only the positions where a variant was found. A listed site with no record in the file is not counted as normal; the report says how many listed sites had no record.

This makes the screen useful as an early flag, ideally before a pre-operative visit, that a known MH-associated variant is present and should be confirmed. It cannot rule MH susceptibility out. Testing for listed variants has a high positive predictive value but poor sensitivity, the absence of a listed variant does not lower the chance of an MH event compared with the general population, and about half of people whose susceptibility was confirmed by contracture testing have no identified variant [1].

How a result is reached

1. Find the listed sites. Each record in the RYR1 and CACNA1S regions is compared with every listed site in the file's own build. Insertions and deletions are normalized against the reference sequence first, so a differently padded record still matches. The alternate allele must match exactly: a different change at the same position does not count.
2. Check each call. A call at a listed site is accepted only if the record's FILTER and the sample's FT are PASS or empty, read depth (DP) is at least 10 and genotype quality (GQ) at least 20, the genotype is complete and diploid, and the reference bases match the reference genome. A missing DP, GQ or FT is reported as unverified but does not block the call. Two records that give different copy numbers for the same variant are treated as a failed call.
3. Give each gene a CPIC phenotype. Malignant Hyperthermia Susceptibility if an accepted call carries at least one copy of an MH-associated variant; No Result if a call at a listed site failed its checks; otherwise Uncertain Susceptibility.
4. Combine the two genes. CPIC's RYR1 and CACNA1S results are read together. Susceptibility in either gene gives the susceptibility recommendation, even if the other gene has no result.

How results appear in the report

The report's anesthesia note opens to the screening details: every listed variant found, with its genotype, zygosity and any quality flags, and the number of listed sites with no record in the file. The seven triggering agents (desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane and succinylcholine) each show one of these labels:

BCHE, which affects how long succinylcholine lasts, is a separate assessment; see succinylcholine.

What the screen does not check

• Variants that aren't in CPIC's tables, including new or private RYR1 and CACNA1S variants. The screen does not classify them.
• Other genes linked to MH, such as STAC3.
• Copy-number changes, large deletions and other structural variants.
• Whether the sequencing covered a listed site that has no record in the file.
• Personal or family history, which CPIC's recommendations assume is absent. A concerning history calls for specialist evaluation, such as clinical genetic testing or a muscle biopsy contracture test, whatever the screen found [1] [4].

Every variant the screen checks

All 348 sites, as listed in CPIC's tables, with their positions on both genome builds. Variant and protein names are as CPIC lists them.

Sources

1. Gonsalves SG et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for the use of potent volatile anesthetic agents and succinylcholine in the context of RYR1 or CACNA1S genotypes. Clin Pharmacol Ther (2019).
2. CPIC. RYR1 allele functionality table (spreadsheet).
3. CPIC. CACNA1S allele functionality table (spreadsheet).
4. Malignant Hyperthermia Association of the United States. Introduction to MH testing.

Informational only, not medical advice. The anesthesia team decides which agents to use.