rs5030847
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP4PP3PM3PS3PM2
This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: PM2: gnomAD MAF: 0.00006; PP3: tools predict damaging ; PS3: 1% residual activity (PMID:25596310; PMID:17935162); PP4: Detection of codon 252arg>trp in a patient with PAH deficiency (PMID:2574153); PM3: Detected with IVS10-11G>A, R261Q, IVS12+1, R68S (all P/LP). (PMID:18299955; PMID:11524738). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PS3, PP4, PM3). LINK:https://erepo.genome.network/evrepo/ui/classification/CA251529/MONDO:0009861/006
Frequency
Consequence
NM_000277.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.754C>T | p.Arg252Trp | missense_variant | 7/13 | ENST00000553106.6 | |
PAH | NM_001354304.2 | c.754C>T | p.Arg252Trp | missense_variant | 8/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.754C>T | p.Arg252Trp | missense_variant | 7/13 | 1 | NM_000277.3 | P1 | |
PAH | ENST00000307000.7 | c.739C>T | p.Arg247Trp | missense_variant | 8/14 | 5 | |||
PAH | ENST00000549247.6 | n.513C>T | non_coding_transcript_exon_variant | 1/6 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152156Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251272Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135792
GnomAD4 exome AF: 0.0000417 AC: 61AN: 1461832Hom.: 0 Cov.: 31 AF XY: 0.0000454 AC XY: 33AN XY: 727222
GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152156Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74326
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:11
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 21, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 15, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 15, 1994 | - - |
Pathogenic, no assertion criteria provided | research | Laboratory of Medical Genetics, University of Torino | Mar 10, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 09, 2024 | - - |
Pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Aug 13, 2018 | PAH-specific ACMG/AMP criteria applied: PM2: gnomAD MAF: 0.00006; PP3: tools predict damaging ; PS3: 1% residual activity (PMID:25596310; PMID:17935162); PP4: Detection of codon 252arg>trp in a patient with PAH deficiency (PMID:2574153); PM3: Detected with IVS10-11G>A, R261Q, IVS12+1, R68S (all P/LP). (PMID:18299955; PMID:11524738). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PS3, PP4, PM3). - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences | Sep 19, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 252 of the PAH protein (p.Arg252Trp). This variant is present in population databases (rs5030847, gnomAD 0.006%). This missense change has been observed in individuals with PAH-associated diseases (PMID: 2574153, 8116675, 17096675, 20082265, 25596310; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 584). 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%. Experimental studies have shown that this missense change affects PAH function (PMID: 12655546, 25596310). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 26, 2018 | Variant summary: PAH c.754C>T (p.Arg252Trp) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.9e-05 in 121328 control chromosomes (ExAC). This frequency is not significantly higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (4.9e-05 vs 0.0079), allowing no conclusion about variant significance. The variant, c.754C>T, has been reported in the literature in numerous individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) in both the compound heterozygous and homozygous states (Aldmiz-Echevarra_2016, Dobrowolski_2011, Jeannesson-Thivisol_2015) and enzyme activity has been reported in patients as <10% of normal activity. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jan 21, 2016 | - - |
not provided Pathogenic:3Other:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 04, 2021 | Classified as a severe variant and reported as homozygous and in the presence of a second PAH pathogenic variant in individuals with classic PKU (Ajami et al., 2003; Desviat et al., 2001; Aulehla-Scholz et al., 2003); Published functional studies demonstrates R252W results in no detectable PAH activity (Pey et al., 2003; Danecka et al., 2015); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Classified as not responsive to BH4 therapy (Zurfluh et al., 2008; Danecka et al., 2015); This variant is associated with the following publications: (PMID: 12655546, 12655553, 17935162, 27535533, 31589614, 1672294, 22513348, 31355225, 30963030, 30037505, 29499199, 9825986, 18294361, 20920871, 11524738, 24301756, 24350308, 23792259, 8304187, 18299955, 8533759, 11461196, 8831077, 10693064, 27264808, 23500595, 2574153, 25750018, 21953985, 25596310, 22975760, 25087612) - |
not provided, no classification provided | literature only | DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 13, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 27, 2018 | The best available variant frequency is uninformative. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Occurs in multiple cases with a recessive pathogenic variant in the same gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. - |
See cases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Oct 04, 2019 | ACMG classification criteria: PS3, PM2, PM3 - |
Pulmonary hypertension, primary, 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 14, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at