Total submissions: 15
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
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, |
RCV000088974 | SCV000281654 | pathogenic | not provided | 2016-05-03 | criteria provided, single submitter | clinical testing | |
Eurofins Ntd Llc |
RCV000088974 | SCV000333001 | pathogenic | not provided | 2015-07-30 | criteria provided, single submitter | clinical testing | |
Gene |
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 |
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, |
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, |
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, |
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, |
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 | |
De |
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, |
RCV000346024 | SCV001455095 | pathogenic | Phenylketonuria | 2020-09-16 | no assertion criteria provided | clinical testing |