rs199475624
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3PM3_StrongPP4_ModeratePM2
This summary comes from the ClinGen Evidence Repository: This c.439C>T (p.Pro147Ser) variant in PAH was reported in at least 5 patients with PAH deficiency, detected with pathogenic variants p.Arg243Gln (PMID:27121329), p.S349P (PMID:15589814), c.1045T>C, c.782G>A (PMID:24941924) and p.A403V (PMID:10234516). DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia (PMID:27121329). This variant is present at an extremely low frequency in gnomAD (MAF=0.00003). Computational evidence for this missense variant supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PP4_moderate, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229541/MONDO:0009861/006
Frequency
Consequence
NM_000277.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.439C>T | p.Pro147Ser | missense_variant, splice_region_variant | 4/13 | ENST00000553106.6 | |
LOC124902999 | XR_007063428.1 | n.808-2415G>A | intron_variant, non_coding_transcript_variant | ||||
PAH | NM_001354304.2 | c.439C>T | p.Pro147Ser | missense_variant, splice_region_variant | 5/14 | ||
PAH | XM_017019370.2 | c.439C>T | p.Pro147Ser | missense_variant, splice_region_variant | 4/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.439C>T | p.Pro147Ser | missense_variant, splice_region_variant | 4/13 | 1 | NM_000277.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251484Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135916
GnomAD4 exome AF: 0.00000206 AC: 3AN: 1459846Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726348
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 16, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jun 01, 2018 | - - |
Likely pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Oct 15, 2020 | This c.439C>T (p.Pro147Ser) variant in PAH was reported in at least 5 patients with PAH deficiency, detected with pathogenic variants p.Arg243Gln (PMID: 27121329), p.S349P (PMID: 15589814), c.1045T>C, c.782G>A (PMID: 24941924) and p.A403V (PMID: 10234516). DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia (PMID: 27121329). This variant is present at an extremely low frequency in gnomAD (MAF=0.00003). Computational evidence for this missense variant supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PP4_moderate, PP3. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 15, 2023 | This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 147 of the PAH protein (p.Pro147Ser). This variant is present in population databases (rs199475624, gnomAD 0.003%). This missense change has been observed in individual(s) with PAH-related conditions (PMID: 10598814, 27121329). ClinVar contains an entry for this variant (Variation ID: 102669). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Pro147 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26322415, 27121329, 31355225). 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, criteria provided, single submitter | clinical testing | 3billion | Feb 23, 2023 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.96; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000102669). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 10234516, 15589814, 24941924, 27121329). A different missense change at the same codon (p.Pro147Leu) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000102670). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 18, 2024 | - - |
not provided Pathogenic:1Other:1
not provided, no classification provided | literature only | DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 30, 2020 | The variant has been reported in several symptomatic phenylketonuria patients in literature (PMIDs: 8981952 (1997), 10234516 (1999), 15589814 (2004), 24941924 (2015), and 27121329 (2016)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is disease causing and damaging. Based on the available information, the variant is predicted to be likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at