Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV001269068 | SCV001448291 | likely pathogenic | Phenylketonuria | 2020-10-16 | reviewed by expert panel | curation | This c.223G>C (p.Asp75His) variant in PAH was reported in 2 patients with PAH deficiency (PMID: 29499199, 28982351) detected with the pathogenic variant p.Val399= (PMID: 28982351). DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia (PMID: 29499199). This variant is absent in population databases. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_moderate, PM3. |
Invitae | RCV001269068 | SCV004296188 | pathogenic | Phenylketonuria | 2022-11-02 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp75 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects PAH function (PMID: 29499199). 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: 987769). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 28982351, 29499199). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 75 of the PAH protein (p.Asp75His). |