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Functional analysis was performed using a <jats:italic>Xenopus laevis<\/jats:italic> oocyte model system.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our cohort of 25 individuals from 22 families with variants in <jats:italic>GABRB2<\/jats:italic> demonstrated a range of epilepsy phenotypes from genetic generalized epilepsy to developmental and epileptic encephalopathy. Fifty\u2010eight percent of individuals had pharmacoresistant epilepsy; response to medications targeting the GABAergic pathway was inconsistent. Developmental disability (present in 84%) ranged from mild intellectual disability to severe global disability; movement disorders (present in 44%) included choreoathetosis, dystonia, and ataxia. Disease\u2010associated variants cluster in the extracellular N\u2010terminus and transmembrane domains 1\u20133, with more severe phenotypes seen in association with variants in transmembrane domains 1 and 2 and the allosteric binding site between transmembrane domains 2 and 3. Functional analysis of 4 variants in transmembrane domains 1 or 2 (p.Ile246Thr, p.Pro252Leu, p.Ile288Ser, p.Val282Ala) revealed strongly reduced amplitudes of GABA\u2010evoked anionic currents.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p><jats:italic>GABRB2<\/jats:italic>\u2010related epilepsy ranges broadly in severity from genetic generalized epilepsy to developmental and epileptic encephalopathies. Developmental disability and movement disorder are key features. The phenotypic spectrum is comparable to other GABA<jats:sub>A<\/jats:sub> receptor\u2010encoding genes. Phenotypic severity varies by protein domain. Experimental evidence supports loss of GABAergic inhibition as the mechanism underlying <jats:italic>GABRB2<\/jats:italic>\u2010associated neurodevelopmental disorders. 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