MAGI2

Inheritance Pattern: AR

Disease ID:MONDO:0033262

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0100062

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0033262

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0019006

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0033262

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0005027

Submitter: ClinGen

*MAGI2* was evaluated for evidence supporting and refuting its relationship with autosomal dominant epilepsy. Of note, variation in *MAGI2* has also been described in association with autosomal recessive nephrotic syndrome. Evidence for this gene-disease relationship is not considered here. *MAGI2* was initially thought to be involved in epilepsy after large deletions including *MAGI2* (and other genes) were reported in individuals with infantile epilepsy (PMIDs: 18565486, 26030165). *MAGI2* was thought to be the causative gene because it has been found to interact with stargazin, a protein that has been associated with epilepsy in mice (PMID: 16870733), and it was the region with the most overlap amongst patients with documented infantile spasms (PMID: 18565486). There have been reports of individuals with deletions at the 7q11.23-7q2.11 locus, where *MAGI2* is located. One individual has a deletion at this locus that spans part of *MAGI2*, but this individual does not have a diagnosis of epilepsy (PMID:18565486). There are also reports of four other individuals with deletions in this region that do not include *MAGI2*, but who have been diagnosed with infantile spasms, suggesting that there is an alternate cause of disease (PMIDs: 21694734, 14636357, 20146355). While some MAGI2 single nucleotide variants have recently been reported in individuals with epilepsy, the genetic testing method used in the paper does not sufficiently rule out other genetic causes of epilepsy, and many variants are present with high allele counts in gnomAD (PMID: 30986657). Furthermore, when considering experimental evidence, *MAGI2* null mouse models have not been reported to present with epilepsy (PMIDs: 25108225, 27932480). Instead, these mice have renal abnormalities consistent with the phenotypic presentation of patients with biallelic intragenic null frameshift variants. This suggests that the absence of *MAGI2* may cause nephrotic syndrome, rather than epilepsy. In summary, the evidence supporting the relationship between *MAGI2* and autosomal dominant epilepsy has been refuted and no valid evidence remains to support the claim. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on October 17, 2023. This gene-disease pair was originally evaluated by the ClinGen Epilepsy Gene Curation Expert Panel on June 19, 2018 and was classified as disputed. In September 2021 and July 2023, it underwent minor administrative updates, but evidence was not reevaluated. Evidence was reevaluated on October 17, 2023. As a result of this reevaluation, the classification did change from disputed to refuted due to a continued lack of valid supporting evidence, and the exclusion of all other new evidence (PMIDs: 25497044, 30986657).