Inheritance

Autosomal dominant

Prevalence

Source:

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD / OMIM

Clinical Validity Scoring Notes and points

Comment from Epilepsy GCEP:

**Note: In September 2021, the ClinGen Epilepsy GCEP opted to change the disease term on this curation from generalised epilepsy to epilepsy. The evidence summary below reflects this change. The original evidence and conclusion remains the same; therefore, the original date of approval has not been changed. **

“CACNA1H was evaluated for evidence supporting and refuting its relationship with the broad phenotype of epilepsy as it has been reported with a variety of phenotypes ranging from childhood absence epilepsy, idiopathic generalized epilepsy and myoclonic astatic epilepsy. CACNA1H has also been described in association with Hyperaldosteronism, familial, type IV, an AD disorder, but evidence for this gene-disease relationship is not considered here. CACNA1H is a voltage-sensitive calcium channel that gives rise to T-type calcium current thought to modulate firing patterns of neurons. CACNA1H has a higher than expected tolerance for missense variants in ExAC and the majority of reported variants have a higher than expected maximum allele frequency for a pathogenic variant. There are no reported de novo pathogenic variants for CACNA1H. Targeted sequencing studies of CACNA1H suggested that missense variants were identified more frequently in patients with childhood absence epilepsy (Chen 2003) and idiopathic generalized epilepsy (Heron 2004, Heron 2007) as compared to control. In Chen 2003, all missense variants were inherited from unaffected parents disputing a clear AD inheritance pattern. In Heron 2004 and Heron 2007, none of the variants segregated consistently with the generalized epilepsy phenotype. CACNA1H is expressed in multiple organ systems and is not unique to the brain (Williams 1999). Whole-cell patch clamp recordings in transfected HEK293 cells with site-directed mutagenesis of identified human CACNA1H missense variants showed inconsistent alteration of channel function (Khosravani 2004, Khosravani 2005, Heron 2007) and no variants were able to be scored as variants with evidence of gene impact. The Genetic Absence Epilepsy Rat from Strausborg (GAERS) has been shown to have a variant in CACNA1H that segregates with seizure expression, however, this is thought to likely represent a polygenic disease model as some rats are null for the variant and still have seizures (Powell 2009). The variant reported in the GAERS model is not reported in human disease. In conclusion, the available genetic and experimental evidence for an AD gene-disease relationship with CACNA1H and epilepsy is insufficient. Variants in CACNA1H are not likely to be causative of epilepsy alone and the gene-disease relationship is Disputed. This curation did not formally examine the hypothesis that CACNA1H is a susceptibility gene, which remains a consideration.”

Variant/Case Evidence:

Segregation Evidence:

Case/Control Evidence:

Experimental Evidence:

Source:

Clinical Validity Points Total

Not a complete curation. Documenting GCEP note for future reference.

Source:

Clinical Validity Classification

Source:

Molecular Mechanism

Loss of function / Gain of function / Dominant Negative

Penetrance

(list source/PMID)

Source:

Age of Onset

(list source/PMID)

Severity

Clinical Features

Sources:

HPO Terms

https://hpo.jax.org/app/

Gene SOPs & Notes

 LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant

Curation Summary

Case ID, Curator name, Date, Jira ticket link