Gamma-aminobutyric acid (GABA) receptors are a group of related proteins that function in the GABAergic neurotransmission of the mammalian central nervous system. GABRB1 is a member of this receptor gene family of ligand-gated ion channels through which GABA, the major inhibitory neurotransmitter in the brain acts. General forms of GABA receptors include two essential α subunits (α1-6), two essential β subunits (β1-3) with one ϒ subunit (ϒ1-3) or one δ subunit. A functional receptor is constituted of an obligatory heterodimer of GABRB1 (β1 subunit) and GABRB2 subunits in which GABRB1 is required for ligand binding and GABRB2 is necessary for interactions with G proteins and increasing the affinity of GABRB1 to GABA [Kaupmann 1998, PMID: 9872317].
GABRB1 was first reported in relation to autosomal dominant developmental and epileptic encephalopathy in 2013 (Epi4K 2013, PMID: 23934111). A single inframe insertion/deletion and 7 missense variants reported in 10 probands across 8 publications are included in this curation (PMIDs: 23934111, 27273810, 31618474, 33994118, 36553572, 37518907, 38024579 and 38633326). Reported features include developmental delay, seizures, hypsarrhythmia, and hypotonia. Even though multiple individuals have been reported, most of these individuals have missense variants without supportive functional evidence; because of this, there is limited evidence to support the relationship between GABRB1 and autosomal dominant developmental and epileptic encephalopathy. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.
This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on August 6, 2024 (SOP version 11).
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