Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000758101 | SCV000886573 | uncertain significance | Phenylketonuria | 2018-12-10 | reviewed by expert panel | curation | The c.650G>A (p.Cys217Tyr) variant in PAH was reported in 1 Japanese PKU patient. DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia. (PMID: 21307867). This variant is absent from ExAC, gnomAD, 1000G, and ESP. A deleterious effect is predicted in SIFT, Polyphen2, MutationTaster, and REVEL=0.982. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate, PP3. |
Fulgent Genetics, |
RCV000758101 | SCV002789155 | uncertain significance | Phenylketonuria | 2021-10-15 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV000758101 | SCV004296173 | pathogenic | Phenylketonuria | 2023-11-14 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 217 of the PAH protein (p.Cys217Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with phenylketonuria (PMID: 21307867, 26322415, 29499199). 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: 102772). 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 PAH protein function with a positive predictive value of 80%. This variant disrupts the p.Cys217 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18798839, 29499199, 32668217). 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. |
De |
RCV000089022 | SCV000119627 | not provided | not provided | no assertion provided | not provided |