CACNA1E

Inheritance Pattern: AD

Disease ID:MONDO:0100062

Submitter: ClinGen

*CACNA1E* encodes the α1 E (Cav2.3) subunit of the high voltage-activated R-type calcium channel that initiates rapid synaptic transmission in the central nervous system. *CACNA1E* was first reported in relation to developmental and epileptic encephalopathy in 2018 (Helbig et al., PMID: 30343943). The main phenotypic features include severe to profound developmental impairment, often with non-verbal and non-ambulatory presentations, severe hypotonia, infantile-onset seizures, and spastic quadriplegia. More variable features include congenital joint contractures, hyperkinetic movement disorders, macrocephaly, developmental regression, autism spectrum disorder, and early death. Five recurrent and/or functionally validated *de novo* missense variants reported in 12 individuals are included in this curation (PMIDs: 30343943, 33776624). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is gain of function (PMID: 30343943). *De novo* missense variants without functional evidence or truncating variants (PMIDs: 30343943, 34702355) were not scored. Additional evidence is needed to clarify the implication of these variants in this condition. In summary, there is definitive evidence to support the relationship between *CACNA1E* and autosomal dominant developmental and epileptic encephalopathy. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on December 6, 2023 (SOP Version 10).

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0032657

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0032657

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0032657

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0032657

Submitter: Illumina

The CACNA1E gene is located on chromosome 1 at 1q25.3 and encodes calcium voltage-gated channel subunit alpha1 E. This subunit is part of the CaV2.3 calcium channel. CaV2.3 channels are widely expressed throughout the central nervous system and conduct voltage-activated, rapidly inactivating R-type calcium currents, which are used to initiate rapid synaptic transmission. CACNA1E was first reported in relation to autosomal dominant developmental and epileptic encephalopathy in 2018 (30343943: Helbig et al. 2018). At least 14 unique missense variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level and experimental data. Variants in this gene have been reported in at least 30 probands in a single multi-institutional publication (30343943: Helbig et al. 2018). In the majority of cases, variants were demonstrated to have occurred de novo. The reported missense variants are also highly clustered in the cytoplasmic ends of all four S6 transmembrane segments, which line the inner pore of the channel and form the activation gate. The mechanism of disease is gain of function; a small number of cases with predicted null variants of uncertain significance have also been reported (30343943: Helbig et al. 2018). This gene-disease relationship is supported by enriched expression in the brain, a shared biochemical function with another gene, CACNA1A, that is associated with a similar early onset epileptic encephalopathy, and in vitro analyses in a human cell line demonstrating and gain of function effect for four missense variants. In summary, there is strong evidence to support the relationship between CACNA1E and autosomal dominant developmental and epileptic encephalopathy. Additional evidence published three years from the first proposal of the association is needed to reach a definitive classification.

Inheritance Pattern: AD

Disease ID:MONDO:0032657

Submitter: Labcorp Genetics (formerly Invitae)