ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.527G>T (p.Arg176Leu)

dbSNP: rs74486803
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 15
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000346024 SCV001448255 pathogenic Phenylketonuria 2020-10-16 reviewed by expert panel curation This c.527G>T (p.Arg176Leu) variant in PAH was reported in multiple patients with hyperphenylalaninemia and detected with 11 pathogenic variants (PMID: 27121329, 9634518, and 29288420). Experimental studies from two publications have demonstrated this variant to have a deleterious effect (PMID: 17924342 and 30037505). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PS3, and PP4_moderate.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics RCV000088974 SCV000281654 pathogenic not provided 2016-05-03 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000088974 SCV000333001 pathogenic not provided 2015-07-30 criteria provided, single submitter clinical testing
GeneDx RCV000088974 SCV000490678 pathogenic not provided 2023-12-18 criteria provided, single submitter clinical testing Considered a mild PAH variant as it is associated with significant residual phenylalanine hydroxylase enzyme activity and has been described in association with mild and moderate PKU and hyperphenylalaninemia (PMID: 17935162, 23500595, 8088845); This variant is associated with the following publications: (PMID: 25087612, 23500595, 34828281, 8088845, 26990548, 31623983, 29997390, 10234516, 27121329, 26210745, 30459323, 31589614, 32668217, 33465300, 29288420, 30037505, 17935162)
Labcorp Genetics (formerly Invitae), Labcorp RCV000346024 SCV000629199 pathogenic Phenylketonuria 2024-01-22 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 176 of the PAH protein (p.Arg176Leu). This variant is present in population databases (rs74486803, gnomAD 0.02%). This missense change has been observed in individual(s) with mild phenylketonuria, classical phenylketonuria and hyperphenylalaninemia (PMID: 8088845, 15464430, 17935162, 23500595, 27121329). ClinVar contains an entry for this variant (Variation ID: 631). 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 not expected to disrupt PAH protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 17924342, 27121329). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001280536 SCV000696454 pathogenic 6-Pyruvoyl-tetrahydrobiopterin synthase deficiency 2020-12-02 criteria provided, single submitter clinical testing Variant summary: PAH c.527G>T (p.Arg176Leu) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251160 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PAH causing Hyperphenylalaninemia (5.2e-05 vs 0.0079), allowing no conclusion about variant significance. c.527G>T has been reported in the literature in multiple individuals affected with Hyperphenylalaninemia (example Aldamiz-Echevarria_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 30%-50% of normal PAH activity (Aldamiz-Echevarria_2016). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000346024 SCV000893950 pathogenic Phenylketonuria 2021-07-26 criteria provided, single submitter clinical testing
Baylor Genetics RCV000346024 SCV001163723 likely pathogenic Phenylketonuria 2024-03-28 criteria provided, single submitter clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002251846 SCV002522779 pathogenic See cases 2021-08-16 criteria provided, single submitter clinical testing ACMG classification criteria: PS3, PM3, PP4
Ambry Genetics RCV002512614 SCV003630104 pathogenic Inborn genetic diseases 2021-08-27 criteria provided, single submitter clinical testing The c.527G>T (p.R176L) alteration is located in exon 6 (coding exon 6) of the PAH gene. This alteration results from a G to T substitution at nucleotide position 527, causing the arginine (R) at amino acid position 176 to be replaced by a leucine (L). Based on data from gnomAD, the T allele has an overall frequency of 0.01% (15/282552) total alleles studied. This alteration has been reported in the compound heterozygous state with a second PAH alteration in several patients with hyperphenylalaninemia and has been reported as a BH4-responsive alteration (Guldberg, 1994; Zurflüh, 2008; Ohlsson, 2017; Aldámiz-Echevarría, 2016). In addition, another alteration at this position (p.R176Q) has also been reported in affected patients (Desviat, 1999; Aldámiz-Echevarría, 2016; Chen, 2018). This amino acid position is not well conserved in available vertebrate species. In vitro functional studies demonstrate reduced residual PAH enzyme activity in multiple cell systems (Gjetting, 2001; Himmelreich, 2018). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
Revvity Omics, Revvity RCV000346024 SCV003822326 pathogenic Phenylketonuria 2022-03-14 criteria provided, single submitter clinical testing
OMIM RCV000000663 SCV000020813 pathogenic Hyperphenylalaninemia 1994-05-15 no assertion criteria provided literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088974 SCV000119577 not provided not provided no assertion provided not provided
Counsyl RCV000346024 SCV000790017 pathogenic Phenylketonuria 2017-03-06 no assertion criteria provided clinical testing
Natera, Inc. RCV000346024 SCV001455095 pathogenic Phenylketonuria 2020-09-16 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.