ClinVar Miner

Submissions for variant NM_130839.5(UBE3A):c.815A>G (p.Asn272Ser) (rs139928148)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory,University of Chicago RCV000144351 SCV000195381 uncertain significance Angelman syndrome 2013-02-08 criteria provided, single submitter clinical testing
GeneDx RCV000519396 SCV000616987 uncertain significance not specified 2015-03-10 criteria provided, single submitter clinical testing A variant of unknown significance has been identified in the UBE3A gene. The N272S variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The N272S variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, but the 1000 Genomes Project reports it was observed in 1/198 (0.5%) alleles from individuals of Kenyan background and in 1/226 (0.4%) alleles from individuals of Gambian ancestry, indicating it may be a rare, benign variant in these populations. This substitution occurs at a position that is conserved across species. However, the N272S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with Angelman syndrome (Stenson et al., 2014). 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 RCV000144351 SCV000754752 uncertain significance Angelman syndrome 2019-11-27 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 252 of the UBE3A protein (p.Asn252Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs139928148, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with UBE3A-related disease. ClinVar contains an entry for this variant (Variation ID: 156141). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Fulgent Genetics,Fulgent Genetics RCV000144351 SCV000896438 uncertain significance Angelman syndrome 2018-10-31 criteria provided, single submitter clinical testing
Baylor Genetics RCV000144351 SCV000188528 uncertain significance Angelman syndrome 2014-02-14 no assertion criteria provided clinical testing possible diagnosis of Angelman syndrome

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