Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000493220 | SCV000582604 | likely pathogenic | not provided | 2016-05-17 | criteria provided, single submitter | clinical testing | The P225S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P225S variant was not observed in approximately 6500 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 P225S 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. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (P225T/L/R) have been reported in the Human Gene Mutation Database in association with ornithine transcarbamylase deficiency (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded |
| Invitae | RCV003621541 | SCV004551950 | likely pathogenic | Ornithine carbamoyltransferase deficiency | 2023-03-28 | 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.Pro225 amino acid residue in OTC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1721894, 9286441, 9427144, 27070778). 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 OTC protein function. ClinVar contains an entry for this variant (Variation ID: 429918). This variant has not been reported in the literature in individuals affected with OTC-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 225 of the OTC protein (p.Pro225Ser). |