Total submissions: 4
| 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. |
| Labcorp Genetics |
RCV000548849 | SCV000629224 | pathogenic | Phenylketonuria | 2023-03-01 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 458082). This missense change has been observed in individual(s) with phenylketonuria (PKU) (PMID: 22333022, 23514811; Invitae). This variant is not present in population databases (gnomAD no frequency). 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). |
| Baylor Genetics | RCV000548849 | SCV004209574 | pathogenic | Phenylketonuria | 2023-09-25 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000548849 | SCV005422078 | pathogenic | Phenylketonuria | 2024-10-25 | criteria provided, single submitter | clinical testing | Variant summary: PAH c.865G>A (p.Gly289Arg) results in a non-conservative amino acid change located in the aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250974 control chromosomes (gnomAD). c.865G>A has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (examples: Aldamiz-Echevarria_JHG_2016, Yan_MBD_2019, internal case). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Another nucleotide change (c.865G>C) resulting in the same amino acid effect has been classified as pathogenic in ClinVar by ClinGen PAH variant curation expert panel (Variation ID: 102882). The following publications have been ascertained in the context of this evaluation (PMID: 27121329, 30747360). ClinVar contains an entry for this variant (Variation ID: 458082). Based on the evidence outlined above, the variant was classified as pathogenic. |