CACNA1H variants are not a cause of monogenic epilepsy

Jeffrey D. Calhoun, Alexandra M. Huffman, Irena Bellinski, Lisa Kinsley, Elizabeth Bachman, Elizabeth Gerard, Jennifer A. Kearney, Gemma L. Carvill*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


CACNA1H genetic variants were originally reported in a childhood absence epilepsy cohort. Subsequently, genetic testing for CACNA1H became available and is currently offered by commercial laboratories. However, the current status of CACNA1H as a monogenic cause of epilepsy is controversial, highlighted by ClinGen's recent reclassification of CACNA1H as disputed. We analyzed published CACNA1H variants and those reported in ClinVar and found none would be classified as pathogenic or likely pathogenic per the American College of Medical Genetics classification criteria. Moreover, Cacna1h did not modify survival in a Dravet Syndrome mouse model. We observed a mild increase in susceptibility to hyperthermia-induced seizures in mice with reduced Cacna1h expression. Overall, we conclude that there is limited evidence that CACNA1H is a monogenic cause of epilepsy in humans and that this gene should be removed from commercial genetic testing panels to reduce the burden of variants of uncertain significance for healthcare providers, families and patients with epilepsy.

Original languageEnglish (US)
Pages (from-to)1138-1144
Number of pages7
JournalHuman mutation
Issue number6
StatePublished - Jun 1 2020


  • epilepsy
  • genetics
  • ion channel
  • seizure

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics


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