Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

CACNA1H : generalised epilepsy

HGNC:1395 | MONDO_0005579
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Epilepsy
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 5

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence Evidence of segregation in one or more families   Sequencing Method 0-3 3
Total LOD Score Canditate Gene Sequencing Exome/Genome or all genes sequenced in linkage region  
2-2.99 0.5 1
3-4.99 1 2
≥5 1.5 3
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Total Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 0
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Function Biochemical Function 0.5 0 - 2 2
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 0.5
Williams ME et al. 1999 Feb (PMID:9930755);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1 1
Heron SE et al. 2007 Dec (PMID:17696120); Khosravani H et al. 2005 May (PMID:15852375);
Models Non-human model organism 2 0 - 4 4 3 3
Cain SM et al. 2018 Apr (PMID:29468672); Talley EM et al. 2000 Jan 10 (PMID:10648900); Powell KL et al. 2009 Jan 14 (PMID:19144837);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 4.5



Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 0 4.5 4.5 NO
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
Moved from Limited to Disputed given lack of evidence for support as a monogenic AD cause of generalized epilepsy.
CACNA1H was evaluated for evidence supporting and refuting its relationship with the broad phenotype of generalized epilepsy (MONDO:0005579) 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 generalized 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.