Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV001200014 | SCV001370873 | likely pathogenic | Phenylketonuria | 2020-03-08 | reviewed by expert panel | curation | The c.674C>T (p.Pro225Leu) variant in PAH has been reported in 2 individuals with PKU (BH4 deficiency excluded (PMID: 21307867). This variant has extremely low frequency in gnomAD MAF=0.000008800. Computational evidence support a deleterious effect. The p.Pro225Thr variant is interpreted as pathogenic. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM5, PP3. |
Labcorp Genetics |
RCV001200014 | SCV005836162 | pathogenic | Phenylketonuria | 2024-09-27 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 225 of the PAH protein (p.Pro225Leu). This variant is present in population databases (rs62517204, gnomAD 0.0009%). This missense change has been observed in individual(s) with phenylketonuria (PMID: 21307867, 32668217; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 932277). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PAH protein function with a positive predictive value of 80%. This variant disrupts the p.Pro225 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18299955, 22330942, 23430547). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |