Adult Summary Report Secondary Findings in Adult Subjects Non-diagnostic, excludes newborn screening & prenatal testing/screening A Current Version Rule-Out Dashboard Release History Status (Adult): Passed (Consensus scoring is Complete) Curation Status (Adult): Released 2.0.1 Status (Pediatric): Passed (Consensus scoring is Complete) P

Condition: Malignant Hyperthermia Susceptibility
Mode(s) of Inheritance: Autosomal Dominant
Actionability Assertion
Gene Condition Pairs(s)
Final Assertion
RYR10018493 (malignant hyperthermia of anesthesia)
Strong Actionability
CACNA1S0018493 (malignant hyperthermia of anesthesia)
Strong Actionability
Actionability Rationale
All experts agreed with the assertion of strong as computed according to the rubric. Though there was a lack of evidence on penetrance and effectiveness, we recognize that defining penetrance and measuring effectiveness of avoidance of the triggering anesthetics in this condition would be a challenge. Though penetrance data was not available for CACNA1S, the potential actionability based on severity and available effective intervention is consistent with strong actionability.
Final Consensus Scoresa
Outcome / Intervention Pair
Nature of the
Gene Condition Pairs: RYR1 0018493 (OMIM:145600) CACNA1S 0018493 (OMIM:601887)
Malignant hyperthermia event / Avoidance of triggering anesthetics
Malignant hyperthermia event / Awareness of high-risk situations

Narrative Description of Evidence
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Condition
The incidence of malignant hyperthermia (MH) is best described by the reported incidence per anesthetic. Incidence estimates for MH range from 1/3000 to 1/500,000 anesthetics. Most report an incidence of about 1/10,000 anesthetics in children and 1/50,000 in adults. MHS has an estimated prevalence of 1/60,000-1/100,000. The prevalence of MH in individuals undergoing surgery in New York state hospitals was estimated as 1/100,000 for adults and 3/100,000 children. However, as many individuals undergoing surgery who experience marked hyperthermia may be coded as being MH susceptible, the exact incidence and prevalence has been difficult to clarify. It seems certain that there are more than 1,000 cases of MH in the US each year.
1 2 3 4 5 6 7 8
Clinical Features
(Signs / symptoms)
MH susceptibility (MHS) is a pharmacogenetic skeletal muscle disorder where exposure to certain volatile anesthetics (i.e., desflurane, enflurane, halothane, isoflurane, sevoflurane), either alone or with a depolarizing muscle relaxant (succinylcholine), may trigger uncontrolled skeletal muscle hypermetabolism. An MH episode may begin with hypercapnia, rapidly rising end-tidal CO2, and tachycardia followed by hyperthermia. Additional symptoms may include acidosis, muscle rigidity, compartment syndrome, rhabdomyolysis and subsequent increased creatine kinase, hyperkalemia with a risk for cardiac arrhythmia or even arrest, and myoglobinuria with a risk for renal failure.
There is mounting evidence that some individuals with MHS may also develop episodes triggered by non-anesthetic conditions such as heat and/or exercise. These non-anesthetic-induced episodes, often called MH-like syndrome, may manifest as exertional rhabdomyolysis (ER). Clinical features are similar to MH and include muscle cramps, elevated temperature, tachycardia, tachypnea, hyperkalemia, and elevated levels of serum myoglobin and creatine kinase. Reports of heat and exercise-induced MH-like reactions in patients with MHS and patients with ER who test positive for MH support an association, though more evidence is needed.
1 3 4 5 6 7 9 10 11
Natural History
(Important subgroups & survival / recovery)
In nearly all cases, the first manifestations of MH occurs during anesthetization in the operating room, though manifestations may also occur within an hour or so of anesthesia termination. MH presentation can vary depending on the triggering agents and environmental factors, such as metabolic state and body temperature, at the beginning of anesthesia. Without proper and prompt treatment with dantrolene, mortality is extremely high, up to 80%. Even with treatment and survival, the individual is at risk for life-threatening consequences and recurrence of the syndrome within the first 24-36 hours following an episode. A study of the North American MH registry showed that nonfatal complications occurred in 35% of affected cases reported from 1987 to 2006. Complications included cardiac, renal, or hepatic dysfunction; coma or change in consciousness; pulmonary edema; and disseminated intravascular coagulation. A significant male preponderance has been reported. All ethnicities are affected.
1 3 4 5 7
2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
The American College of Medical Genetics and Genomics (ACMG) has developed an ACT sheet to help clinical decision-making following identification of RYR1 and/or CACNA1S pathogenic variant(s) as a secondary finding:
Surgical management recommendations include preparation of the anesthesia workstation to reduce or prevent exposure to triggering anesthetics (e.g., remove vaporizers from machine and replace all disposables), vigilant monitoring for signs and symptoms of MH during perioperative period, and close observation and monitoring postoperatively. (Tier 3)
7 8
If a pregnant woman with MHS requires non-emergent surgery, a non-triggering anesthetic (local, nerve block, epidural, spinal anesthesia or a total intravenous general anesthetic) should be administered. Continuous epidural analgesia is highly recommended for labor and delivery. If a Cesarean delivery is indicated in a woman who does not have an epidural catheter in place, neuraxial (spinal, epidural, or combined spinalepidural) anesthesia is recommended, if not otherwise contraindicated. If a general anesthetic is indicated, a total intravenous anesthetic technique should be administered, with an anesthesia machine that has been prepared for an MH-susceptible individual. (Tier 4)
MHS patients should carry identification of their susceptibility and inform those responsible for their care of their MH status. (Tier 2)
No surveillance recommendations have been provided for the Adult context.
Circumstances to Avoid
Do not use the following MH triggering drugs for MHS patients: inhaled general anesthetics (desflurane, enflurane, halothane, isoflurane, sevoflurane) and depolarizing muscle relaxants (succinylcholine). (Tier 2)
3 7 8
MHS patients who have not experienced adverse effects of heat and exercise should not restrict their activity. However, athletes with MHS should develop an MH-specific emergency action plan and prepare an on-site cooling plan. Athletes with MHS should not exercise alone and should notify their medical providers (e.g., athletic trainer, team physician) about the condition. Those who have experienced adverse effects of heat or exercise should restrict their activity based on their own experience. (Tier 2)
5 10
In individuals with MH undergoing cardiac bypass surgery, aggressive rewarming should be avoided, as it is associated with development of clinical signs of MH. (Tier 3)
Serotonin antagonist (5HT3-antagonist) antiemetics should be used cautiously. Sudden death was reported in a child with multiminicore disease caused by a pathogenic variant in RYR1 after receiving a therapeutic dose of ondansetron. (Tier 3)
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Dominant
1 3 4 5 6 11
Prevalence of Genetic Variants
Pathogenic variants in RYR1 are identified in up to 50-75% of MHS cases, while pathogenic variants in CACNA1S account for about 1% of cases. (Tier 3)
1 5 7
A systematic review identified MH-related pathogenic variants in RYR1 and CACNA1S in 78% of patients with a history of ER. (Tier 1)
For RYR1, one study identified a prevalence of 0.46% (4/870) for MHS-related RYR1 pathogenic variants. In a second study, based on genetic variation data of more than 60,000 individuals, the combined prevalence of MHS-related RYR1 pathogenic variants was estimated as 1/2750. (Tier 3)
1 5
One study used RYR1 and CACNA1S genomic databases to estimate the prevalence of an MHS-related pathogenic variant as 1/1556. (Tier 3)
(Include any high risk racial or ethnic subgroups)
In a multicenter case-control study from 125 MH pedigrees, the overall penetrance for RYR1-related MHS was 40.6%. Penetrance was based on the number of probands who were survivors of an MH event among all genotype-positives who had at least one exposure to a triggering anesthetic. Proband median age was 12 years. Penetrance in males was significantly higher than in females (50% vs. 29.7%, p=0.002). (Tier 3)
The penetrance of MHS associated with CACNA1S is unknown.
Relative Risk
(Include any high risk racial or ethnic subgroups)
Information on relative risk was not available.
An MH episode may not occur with every exposure to "trigger" agents. Clinical manifestation may depend on genetic predisposition, dose of trigger agents, or duration of exposure. (Tier 4)
A genetically susceptible patient may manifest clinical signs at any point in their life. (Tier 3)
4. What is the Nature of the Intervention?
Nature of Intervention
The interventions identified include avoidance of certain anesthetic agents and potential avoidance of heat and heavy exercise. These interventions are mildly burdensome and pose minimal risk.
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
Under usual care, a patient may be exposed to a triggering anesthetic agent which could result in high morbidity or potential mortality. However, it should be noted that modern anesthetic care and monitoring often allow early detection of MH. (Tier 4)
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.

Gene Condition Associations
Condition Associations
OMIM Identifier
Primary MONDO Identifier
Additional MONDO Identifiers
Reference List
1. H Rosenberg, N Sambuughin, S Riazi, R Dirksen. Malignant Hyperthermia Susceptibility. 2003 Dec 19 [Updated 2013 Jan 31]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from:
2. Rosenberg H, Rueffert H. Clinical utility gene card for: malignant hyperthermia. Eur J Hum Genet. (2011) 19(6).
3. Gurunluoglu R, Swanson JA, Haeck PC. Evidence-based patient safety advisory: malignant hyperthermia. Plast Reconstr Surg. (2009) 124(4 Suppl):68S-81S.
4. Malignant hyperthermia. Orphanet encyclopedia,
5. Hosokawa Y, Casa DJ, Rosenberg H, Capacchione JF, Sagui E, Riazi S, Belval LN, Deuster PA, Jardine JF, Kavouras SA, Lee EC, Miller KC, Muldoon SM, O'Connor FG, Sailor SR, Sambuughin N, Stearns RL, Adams WM, Huggins RA, Vandermark LW. Round Table on Malignant Hyperthermia in Physically Active Populations: Meeting Proceedings. J Athl Train. (2017) 52(1938-162X):377-383.
6. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MALIGNANT HYPERTHERMIA, SUSCEPTIBILITY TO, 1; MHS1. MIM: 145600: 2017 Mar 02. World Wide Web URL:
7. . JSA guideline for the management of malignant hyperthermia crisis 2016. J Anesth. Journal of anesthesia. (2017) 31(1438-8359):307-317.
8. Urman RD, Rajan N, Belani K, Gayer S, Joshi GP. Malignant Hyperthermia-Susceptible Adult Patient and Ambulatory Surgery Center: Society for Ambulatory Anesthesia and Ambulatory Surgical Care Committee of the American Society of Anesthesiologists Position Statement. Anesth Analg. (2019) 129(1526-7598):347-349.
9. Kraeva N, Sapa A, Dowling JJ, Riazi S. Malignant hyperthermia susceptibility in patients with exertional rhabdomyolysis: a retrospective cohort study and updated systematic review. Can J Anaesth. (2017) 64(1496-8975):736-743.
10. Litman RS, Smith VI, Larach MG, Mayes L, Shukry M, Theroux MC, Watt S, Wong CA. Consensus Statement of the Malignant Hyperthermia Association of the United States on Unresolved Clinical Questions Concerning the Management of Patients With Malignant Hyperthermia. Anesth Analg. (2019) 128(1526-7598):652-659.
11. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MALIGNANT HYPERTHERMIA, SUSCEPTIBILITY TO, 5; MHS5. MIM: 601887: 2020 Apr 01. World Wide Web URL:
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