ClinVar Miner

Submissions for variant NM_130839.5(UBE3A):c.1176A>T (p.Glu392Asp) (rs587784510)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory,University of Chicago RCV000147861 SCV000195335 uncertain significance Angelman syndrome 2013-10-10 criteria provided, single submitter clinical testing
GeneDx RCV000523791 SCV000617193 uncertain significance not provided 2015-10-30 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the UBE3A gene. The E372D variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E372D variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000147861 SCV000948884 uncertain significance Angelman syndrome 2018-11-09 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 372 of the UBE3A protein (p.Glu372Asp). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with UBE3A-related disease. ClinVar contains an entry for this variant (Variation ID: 160200). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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