ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.662A>G (p.Glu221Gly)

dbSNP: rs62514934
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000000640 SCV001370848 likely pathogenic Phenylketonuria 2020-05-22 reviewed by expert panel curation The c.662A>G (p.Glu221Gly) variant in PAH has been reported in multiple individuals with mild PKU (BH4 deficiency excluded) and MHP. (PMID: 1679030 8860005 10947211). It was detected in trans with pathogenic variant L48S and in the homozygous state. This variant has extremely low frequency in ExAC (0.00001) and gnomAD (0.000004064). Computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3.
Labcorp Genetics (formerly Invitae), Labcorp RCV000000640 SCV004296172 pathogenic Phenylketonuria 2023-06-04 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 221 of the PAH protein (p.Glu221Gly). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PAH protein function. ClinVar contains an entry for this variant (Variation ID: 609). This missense change has been observed in individual(s) with mild hyperphenylalaninemia and/or phenylketonuria (PMID: 1679030, 10947211, 32668217). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs62514934, gnomAD 0.0009%).
OMIM RCV000000640 SCV000020790 pathogenic Phenylketonuria 1991-08-01 no assertion criteria provided literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089024 SCV000119629 not provided not provided no assertion provided not provided

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.