CACNA1S was first reported in relation to autosomal dominant malignant hyperthermia in 1997 (Monnier et al., PMID:9199552) and assigned the name “Malignant Hyperthermia susceptibility 5 (OMIM:601887). This condition is a muscle disorder in which an episode is triggered by exposure to volatile anesthetic agents or depolarizing muscle relaxants (i.e., halothane, isoflurane, sevoflurane, desflurane, enflurane) either alone or in conjunction with a depolarizing muscle relaxant, leading to muscle rigidity and a hypermetabolic response involving elevated temperature, heart rate, and respiratory rate that can be fatal if not recognized and treated promptly.
CACNA1S has been noted to be associated with the following disease entities: Hypokalemic periodic paralysis, type 1 (OMIM:170400), Malignant hyperthermia susceptibility 5 (OMIM:601887), Thyrotoxic periodic paralysis, susceptibility to,1 (OMIM:188580). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanisms, inheritance patterns, and phenotypic variability. Therefore, we have maintained the existing split into multiple disease entities. In addition, there is a more recent assertion for Congenital myopathy 18 due to dihydropyridine receptor defect (OMIM: 620246) that was not considered at the time of the precuration (9/15/2022). In this curation we examine autosomal dominant Malignant hyperthermia susceptibility 5 as a distinct disease entity.
Evidence supporting this gene-disease relationship includes case-level data, segregation data, experimental data. We have curated eight pathogenic missense variants reported in ten probands, two of which (p.R1086H, p.T1354S) were found to segregate in families (PMID: 9199552, 11260227, 20861472,25658027,25735680,19825159). A novel homozygous mutation, p.Arg1086Ser, was identified in a 34 year old female who developed fulminant malignant hyperthermia (MH) under sevoflurane anesthesia. This is the only homozygous occurrence mentioned in the literature to date and it is unclear whether it represents a distinct molecular mechanism of disease (PMID:.20431982)
This gene-disease association is supported by in vitro functional assays, expression studies, animal models, rescue models (PMID: 27129199, 2903448, 7713519, 15201141, 6329263). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.