CACNG2

Inheritance Pattern: AD

Disease ID:MONDO:0013657

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*CACNG2* encodes an AMPA receptor regulatory protein involved in synaptic plasticity. *CACNG2* was first reported in relation to autosomal dominant intellectual disability in 2011 (Hamdan et al., PMID: 21376300). Later, rare *de novo* variants in *CACNG2* were also reported in probands with epilepsy and autism spectrum disorder (ASD). Due to the variable presentation in the reported probands, we decided to curate for the generic term complex neurodevelopmental disorder. Evidence supporting this gene-disease relationship is minimal. Only three patients with non-overlapping phenotypes have been reported to carry rare variants in *CACNG2*, with insufficient evidence for disease causality. A *de novo* missense variant was reported in a patient with moderate intellectual disability and no epilepsy; functional studies of the variant showed reduced binding to AMPA receptors and decreased glutamatergic transmission (Hamdan et al., PMID: 21376300). A *de novo* microdeletion encompassing exon 2 of *CACNG2* and resulting in an in-frame deletion was reported in an individual with ASD (Brandler et al., PMID: 27018473). In addition, a *de novo* splice site variant was reported in a patient with focal Rolandic seizures and borderline IQ (Rudolf et al., PMID: 32600977). *CACNG2* is intolerant to truncating variants (pLI = 1, LOEUF = 0.3; gnomAD v4.1.1) but is not significantly constrained for missense variants (Z = 1.88). This gene-disease relationship is also supported by experimental evidence. Knock-in mice harboring the V143L missense variant reported in a patient with intellectual disability exhibit cognitive and social deficits, and impaired spine maturation, abnormal synaptic transmission and long-term potentiation specifically in basal dendrites of hippocampal CA1 neurons (PMID: 35256745). In addition, two mouse models homozygous for spontaneous mutations disrupting *Cacng2* exhibit ataxic gait and absence seizures, together with defects in the cerebellum and inner ear (PMIDs: 12925883, 15283975). The relevance of these phenotypes to those observed in individuals with heterozygous *CACNG2* variants is unclear, so this experimental evidence was not scored. In summary, there is limited evidence to support the relationship between *CACNG2* and autosomal dominant complex neurodevelopmental disorder. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on July 7, 2021. It was reevaluated on August 24, 2026 (SOP Version 12). Although a new mouse model was published (PMID: 35256745), no additional patients were identified and the classification did not change.

Inheritance Pattern: Unknown

Disease ID:MONDO:0013657

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0015802

Submitter: Orphanet