ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1124A>G (p.Gln375Arg)

gnomAD frequency: 0.00001  dbSNP: rs1874694173
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV001199982 SCV001370809 uncertain significance Phenylketonuria 2020-06-19 reviewed by expert panel curation The c.1124A>G (p.Gln375Arg) variant in PAH has been reported in an Iranian patient with mild PKU (PMID: 24301756). This variant is absent in population databases. A deleterious effect is predicted in SIFT, Polyphen-2, and MutationTaster. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PP3.
Labcorp Genetics (formerly Invitae), Labcorp RCV001199982 SCV002248290 likely pathogenic Phenylketonuria 2022-02-11 criteria provided, single submitter clinical testing This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 375 of the PAH protein (p.Gln375Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of hyperphenylalaninemia (PMID: 24301756, 31130284). ClinVar contains an entry for this variant (Variation ID: 932257). 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. This variant disrupts the p.Gln375 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28982351, 29499199). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.