ClinVar Miner

Submissions for variant NM_130839.5(UBE3A):c.175C>T (p.Arg59Cys)

gnomAD frequency: 0.00001  dbSNP: rs587783098
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000144764 SCV000190980 uncertain significance not provided 2014-08-22 criteria provided, single submitter clinical testing The R59C variant has not been published as a mutation, nor has it been reported as a benign polymorphism 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 R59C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico analysis predicts this variant is probably damaging to the protein structure/function. This substitution occurs at a position that is conserved among mammals; however, Cysteine is observed at this position in one mammalian species. This variant has been observed to be paternally inherited. The variant is found in CHILD-EPI panel(s).
Invitae RCV002512563 SCV003445398 uncertain significance Angelman syndrome 2023-05-24 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 39 of the UBE3A protein (p.Arg39Cys). This variant is present in population databases (rs587783098, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with UBE3A-related conditions. ClinVar contains an entry for this variant (Variation ID: 156621). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on UBE3A protein function. Experimental studies have shown that this missense change does not substantially affect UBE3A function (PMID: 34815418). 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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