Submission Details

GABRB3 was first reported in relation to autosomal dominant developmental and epileptic encephalopathy in 2016 (Epi4K Consortium et al., 27476654). Evidence supporting this gene-disease relationship includes case-level and experimental data. Many de novo missense variants have been reported in humans, which reaches the maximum score for genetic evidence (Epi4K Consortium et al. 2016, 27476654; Zhang et al. 2015, 26544041; Le et al. 2017, 28544625; Sterbova et al. 2018, 29444535). This gene-disease association is supported by functional alteration evidence and mouse models (Janve et al. 2016, 26950270; Hernandez et al. 2017, 29162865; Moller et al. 2017, 28053010; DeLorey et al. 2008, 17983671; Ferguson et al. 2007; 17927825). A global knockout and a forebrain selective knockout mouse model were each scored for replicating seizure phenotypes, but were downgraded because the homozygous models do not replicate the heterozygous mechanism observed in humans. Of note, missense variants have been reported to segregate in three families with familial GEFS+. One affected individual of each family is likely a phenocopy, as they do not carry the reported GABRB3 variant (Moller et al. 2017, 28053010). These families were not curated as part of the GABRB3-autosomal dominant developmental epileptic encephalopathy. In summary, GABRB3 is definitively associated with autosomal dominant developmental epileptic encephalopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on 2/5/2019.