Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV002260624 | SCV002540709 | uncertain significance | Angelman syndrome | 2022-06-30 | reviewed by expert panel | curation | The c.139A>G p.(Ile47Val) variant in UBE3A (NM_130838.2) is present in gnomAD v2.1.1 at a frequency of 0.00088% in the European non-Finnish sub population (no criteria met). The p.(Ile47Val) variant has been observed in at least 3 individuals with neurodevelopmental phenotypes consistent with UBE3A-related disease (ClinVar SCV000191055.4, SCV001445014.1); however, PS4 cannot be applied due to the gnomAD frequency. Computational analysis prediction tools suggest that the p.(Ile47Val) variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the c.139A>G p.(Ile47Val) variant in UBE3A is classified as a Variant of Uncertain Significance based on the ACMG/AMP criteria (BP4). |
| Gene |
RCV000144820 | SCV000191055 | likely pathogenic | not provided | 2017-11-09 | criteria provided, single submitter | clinical testing | A variant that is likely pathogenic has been identified in the UBE3A gene. The I67V variant has not been published as a pathogenic variant, 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. This substitution occurs at a position that is conserved in mammals but is not conserved in more distant species. The I67V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis predicts this variant likely does not alter the protein structure/function. However, targeted parental testing indicates this variant is apparently de novo. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. |
| Ambry Genetics | RCV001266834 | SCV001445014 | uncertain significance | Inborn genetic diseases | 2017-11-15 | criteria provided, single submitter | clinical testing |