Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000483765 | SCV000570400 | likely pathogenic | not provided | 2016-06-08 | criteria provided, single submitter | clinical testing | The R506H variant has not been published as a pathogenic variant, nor has it been reported as a benignvariant to our knowledge. However, a different missense variant at the same position (R506C) hasbeen reported multiple times previously in association with Angelman syndrome (Baumer et al.,1999; Camprubi et al., 2009; Carvill et al., 2013). The R506H variant was not observed inapproximately 6,500 individuals of European and African American ancestry in the NHLBI ExomeSequencing Project, indicating it is not a common benign variant in these populations. Thissubstitution occurs at a position that is conserved across species. In silico analysis predicts thisvariant is probably damaging to the protein structure/function. However, the R506H variant is aconservative amino acid substitution, which is not likely to impact secondary protein structure asthese residues share similar properties. Therefore, this variant is likely pathogenic; however, thepossibility that it is benign cannot be excluded. |
| Mendelics | RCV000989273 | SCV001139529 | likely pathogenic | Angelman syndrome | 2019-05-28 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV001266187 | SCV001444359 | likely pathogenic | Inborn genetic diseases | 2017-12-18 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000989273 | SCV002152268 | likely pathogenic | Angelman syndrome | 2022-11-29 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg506 amino acid residue in UBE3A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19213023, 26255772). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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) performed at Invitae indicates that this missense variant is expected to disrupt UBE3A protein function. ClinVar contains an entry for this variant (Variation ID: 421257). This variant has not been reported in the literature in individuals affected with UBE3A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine with histidine at codon 506 of the UBE3A protein (p.Arg506His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. |