Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000548849 | SCV001448292 | pathogenic | Phenylketonuria | 2020-10-16 | reviewed by expert panel | curation | This c.865G>A (p.Gly289Arg) variant in PAH was reported in 2 patients with PAH deficiency (PMID: 27121329) detected with the pathogenic variant p.Gly272* and the likely pathogenic variant p.Arg155Cys. DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia. This variant has the same amino acid change as a previously established pathogenic variant in ClinVar (Variation ID: 102882). This variant is absent in population databases. Computational evidence for this missense variant supports a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PS1, PM2, PP4_moderate, PM3, PP3. |
Invitae | RCV000548849 | SCV000629224 | pathogenic | Phenylketonuria | 2023-03-01 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 289 of the PAH protein (p.Gly289Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with phenylketonuria (PKU) (PMID: 22333022, 23514811; Invitae). ClinVar contains an entry for this variant (Variation ID: 458082). 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. For these reasons, this variant has been classified as Pathogenic. |
Baylor Genetics | RCV000548849 | SCV004209574 | pathogenic | Phenylketonuria | 2023-09-25 | criteria provided, single submitter | clinical testing |