rs75166491
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PP3PS3PM3_StrongPP4_ModeratePM2
This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency. ExAC MAF=0.00019.; PP3: Predicted deleterious in SIFT, Polyphen-2, MutationTaster. REVEL=0.939; PS3: 2% mutant enzyme activity in BioPKU; PP4_Moderate: Detected in at least 3 patients with PAH deficiency. BH4 deficiency ruled out in 1 patient. (PMID:1307609; PMID:10429004; PMID:9634518); PM3_Strong: Detected with 3 pathogenic/likely pathogenic variants (PMID:14681498; PMID:23430918). 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_Moderate, PM3_Strong). LINK:https://erepo.genome.network/evrepo/ui/classification/CA229570/MONDO:0009861/006
Frequency
Consequence
NM_000277.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.472C>T | p.Arg158Trp | missense_variant | 5/13 | ENST00000553106.6 | |
LOC124902999 | XR_007063428.1 | n.807+1406G>A | intron_variant, non_coding_transcript_variant | ||||
PAH | NM_001354304.2 | c.472C>T | p.Arg158Trp | missense_variant | 6/14 | ||
PAH | XM_017019370.2 | c.472C>T | p.Arg158Trp | missense_variant | 5/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.472C>T | p.Arg158Trp | missense_variant | 5/13 | 1 | NM_000277.3 | P1 | |
PAH | ENST00000549111.5 | n.568C>T | non_coding_transcript_exon_variant | 5/6 | 1 | ||||
PAH | ENST00000307000.7 | c.457C>T | p.Arg153Trp | missense_variant | 6/14 | 5 | |||
PAH | ENST00000551988.5 | n.530+10829C>T | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152136Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251352Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135836
GnomAD4 exome AF: 0.0000185 AC: 27AN: 1461492Hom.: 0 Cov.: 30 AF XY: 0.0000179 AC XY: 13AN XY: 727066
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152136Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74322
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:8
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 12, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant c.472C>T (p.Arg158Trp) in PAH gene has been reported as homozygous or in combination with another PAH variant in multiple individuals affected with phenylketonuria (Santos LL et.al.,2010). Functional analysis found that R158W is associated with 1.8% residual enzyme activity compared to wild type (Danecka et al.,2015). This variant has been reported to the ClinVar database as Pathogenic. The p.Arg158Trp variant is reported with allele frequency 0.003% in gnomAD exomes and novel in 1000 Genomes. The amino acid Arg at position 158 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg158Trp in PAH is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic . - |
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 10, 2018 | PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency. ExAC MAF=0.00019.; PP3: Predicted deleterious in SIFT, Polyphen-2, MutationTaster. REVEL=0.939; PS3: 2% mutant enzyme activity in BioPKU; PP4_Moderate: Detected in at least 3 patients with PAH deficiency. BH4 deficiency ruled out in 1 patient. (PMID:1307609; PMID:10429004; PMID:9634518); PM3_Strong: Detected with 3 pathogenic/likely pathogenic variants (PMID:14681498; PMID:23430918). 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_Moderate, PM3_Strong). - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 08, 2022 | Variant summary: PAH c.472C>T (p.Arg158Trp) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) 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 2.8e-05 in 251352 control chromosomes (gnomAD). c.472C>T has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Shintaku_2003, Santos__2010, Jeannesson-Thivisol_2015). These data indicate that the variant is very likely to be associated with disease. At least one functional study reports this variant effect results in <10% of normal activity (Danecka_2015). In addition, another variant (p.Arg158Gln) at the same residue was found in many individuals affected Phenylketonuria and has been classified as pathogenic at our laboratory, indicating the arginine residue is critical for protein function. Five ClinVar submitters (evaluation after 2014, including one expert panel, ClinGen PAH Variant Curation Expert Panel) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jan 21, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 158 of the PAH protein (p.Arg158Trp). This variant is present in population databases (rs75166491, gnomAD 0.01%). This missense change has been observed in individual(s) with phenylketonuria (PKU) (PMID: 10356314, 14681498, 19609714, 20082265, 23430918, 24130151, 24941924, 25894915, 26666653). ClinVar contains an entry for this variant (Variation ID: 102693). 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.Arg158 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2014036, 10479481, 23500595, 24368688, 25596310). 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. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided Pathogenic:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 22, 2021 | Reported homozygous in an individual with mild-moderate PKU (Jeannesson-Thivisol et al., 2015); however, this variant has also been identified in individuals with classic PKU (Yamashita et al., 1992; Bashyam et al., 2014; Jeannesson-Thivisol et al., 2015; Danecka et al., 2015); Published functional studies demonstrate p.(R158W) results in significantly reduced residual activity compared to wildtype (Danecka et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25750018, 34828281, 29413232, 25087612, 25596310, 1307609, 26666653, 24130151, 29499199, 30747360, 30275481, 32668217, 32778825, 33375644, 17935162, 17924342) - |
not provided, no classification provided | literature only | DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at