Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001379708 | SCV001577556 | likely pathogenic | Phenylketonuria | 2023-09-08 | criteria provided, single submitter | clinical testing | 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 not expected to disrupt PAH protein function. ClinVar contains an entry for this variant (Variation ID: 1068222). This variant has not been reported in the literature in individuals affected with PAH-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 287 of the PAH protein (p.Leu287Met). This variant disrupts the p.Leu287 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12409276, 16198137). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. |