The UBE3B gene is located on chromosome 12 at 12q24.11 and encodes ubiquitin protein ligase E3B. The UBE3B gene product plays a role in protein degradation by the ubiquitin proteasome system, which helps to regulate protein levels and remove damaged or abnormal proteins. UBE3B was first reported in relation to autosomal recessive Kaufman oculocerebrofacial syndrome in 2012 (Basel-Vanagaite et al., PMID 23200864). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included twelve unique variants (3 missense, 1 start-lost, 2 splice, 4 stop-gained, 2 frameshift) reported in ten unrelated probands in four publications (Basel-Vanagaite et al., 2012 PMID 23200864; Flex et al., 2013 PMID 23687348; Basel-Vanagaite et al., 2014 PMID 24615390; Pedurupillay et al., 2015 PMID 25691420). The missense variants were located in the functionally important HECT domain, but the functional consequence of these variants were not demonstrated experimentally. In one case, experimental studies suggested a mutant transcript escaped from nonsense-mediated decay. Variants in this gene segregated with disease in three additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is supported by a shared biochemical function (ubiquitin-proteasome system) with at least one other gene associated with an intellectual disability syndrome (UBE3A:Angelman syndrome), developmental expression in the central nervous system and craniofacial structures consistent with the disease, and a homozygous null mouse model that recapitulates diverse clinical features observed in human patients (Basel-Vanagaite et al., 2012 PMID 23200864). In summary, UBE3B is definitively associated with autosomal recessive Kaufman oculocerebrofacial syndrome. This relationship 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 Syndromic Disorders Gene Curation Expert Panel on the meeting date 6Jan2021 (SOP Version 8).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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