Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000169393 | SCV004222613 | pathogenic | Phenylketonuria | 2023-12-30 | reviewed by expert panel | curation | The c.1301C>A (p.Ala434Asp) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). PMID: 16256386, 21147011). This variant is absent in population databases. Residual enzyme activity of the p.A434D mutant is 21.7% of wild type, and the formation and stability of the PAH protein was affected (PMID: 18247293). This variant was detected with pathogenic variants: p.R252Q, p.R243Q (PMID: 16256386); p.E390G, p.R261Q (PMID: 21147011); p.R243Q (3 patients); IVS4-1G>A (2 patients); p.E280K, p.R111X (PMID: 23932990). Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PP4_Moderate, PS3_supporting, PM2_supporting, PP3. |
Counsyl | RCV000169393 | SCV000220785 | likely pathogenic | Phenylketonuria | 2014-10-13 | criteria provided, single submitter | literature only | |
Labcorp Genetics |
RCV000169393 | SCV001579238 | pathogenic | Phenylketonuria | 2024-07-12 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 434 of the PAH protein (p.Ala434Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with phenylketonuria (PMID: 16256386, 18247293, 24401910, 27264808, 29499199). ClinVar contains an entry for this variant (Variation ID: 102586). 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%. Experimental studies have shown that this missense change affects PAH function (PMID: 30037505). For these reasons, this variant has been classified as Pathogenic. |
Baylor Genetics | RCV000169393 | SCV004209615 | pathogenic | Phenylketonuria | 2023-11-10 | criteria provided, single submitter | clinical testing | |
Juno Genomics, |
RCV000169393 | SCV005417750 | pathogenic | Phenylketonuria | criteria provided, single submitter | clinical testing | PM2_Supporting+PS3_Supporting+PM3_VeryStrong | |
De |
RCV000088825 | SCV000119416 | not provided | not provided | no assertion provided | not provided | ||
Natera, |
RCV000169393 | SCV002088616 | pathogenic | Phenylketonuria | 2021-07-29 | no assertion criteria provided | clinical testing |