Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV001199992 | SCV001370830 | pathogenic | Phenylketonuria | 2020-05-14 | reviewed by expert panel | curation | The c.505C>A (p.Arg169Ser) variant in PAH is detected in 4 Chinese patients with Phe levels >120 umol/l (PMID 26503515, 30747360, 30050108, 28982351 ) (PP4-Moderate). The variant was detected in trans with pathogenic variants p.R241C, p.R413P, R408Q, p.R243Q (PMID: 30050108, 28982351). The validation tests on parents were performed using Sanger sequencing (PM3-Very Strong). This variant is absent from controls in gnomAD, PAGE, 100 Genomes or ESP (PM2). This variant is predicted to be damaging in SIFT, PolyPhen2, and MutationTaster. REVEL score = 0.805 (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4-Moderate, PM3-Very Strong, PP3. |
| Labcorp Genetics |
RCV001199992 | SCV002246020 | pathogenic | Phenylketonuria | 2023-12-09 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 169 of the PAH protein (p.Arg169Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with phenylketonuria (PMID: 25449068, 26503515, 28982351, 30459323). ClinVar contains an entry for this variant (Variation ID: 932262). 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 with a negative predictive value of 80%. This variant disrupts the p.Arg169 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10234516, 18299955, 21147011, 26666653, 28982351). 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. |
| Baylor Genetics | RCV001199992 | SCV004209567 | pathogenic | Phenylketonuria | 2024-01-24 | criteria provided, single submitter | clinical testing | |
| Juno Genomics, |
RCV001199992 | SCV005418282 | pathogenic | Phenylketonuria | criteria provided, single submitter | clinical testing | PM2_Supporting+PP3+PM3_VeryStrong+PP4_Moderate+PM5 |