ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.464G>C (p.Arg155Pro)

dbSNP: rs199475663
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000675156 SCV000852116 likely pathogenic Phenylketonuria 2018-08-10 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PM2: absent from ExAC, gnomAD, 1000G, ESP. PAGE MAF=0.00066; PP3: Deleterious effect predicted in SIFT, Polyphen-2, MutationTaster. REVEL=0.967; PP4_Moderate: Detected in a patient with classic PKU. Cofactor deficiency excluded. (PMID:10679941); PM3: Detected in trans with R408W (P) (PMID:10679941). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PP4_Moderate, PM3).
Eurofins Ntd Llc (ga) RCV000088935 SCV000230889 uncertain significance not provided 2015-09-29 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000675156 SCV003441289 pathogenic Phenylketonuria 2024-03-10 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 155 of the PAH protein (p.Arg155Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 10679941, 26666653). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 102687). 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 with a positive predictive value of 80%. This variant disrupts the p.Arg155 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23514811). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088935 SCV000119535 not provided not provided no assertion provided not provided
Counsyl RCV000675156 SCV000800771 likely pathogenic Phenylketonuria 2017-06-20 no assertion criteria provided clinical testing

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.