rs199475694
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong
The NM_000277.3(PAH):c.440C>T(p.Pro147Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P147S) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000277.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.440C>T | p.Pro147Leu | missense_variant, splice_region_variant | 4/13 | ENST00000553106.6 | |
LOC124902999 | XR_007063428.1 | n.808-2416G>A | intron_variant, non_coding_transcript_variant | ||||
PAH | NM_001354304.2 | c.440C>T | p.Pro147Leu | missense_variant, splice_region_variant | 5/14 | ||
PAH | XM_017019370.2 | c.440C>T | p.Pro147Leu | missense_variant, splice_region_variant | 4/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.440C>T | p.Pro147Leu | missense_variant, splice_region_variant | 4/13 | 1 | NM_000277.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 21, 2018 | - - |
Likely pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Apr 09, 2019 | The c.440C>T (p.Pro147Leu) variant in PAH has been reported in multiple individuals with mild PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 27121329, 26322415, 16527067, 30050108, 28982351). This variant is absent in population databases (PM2). This variant was detected in trans with known pathogenic variants p.R261Ter (PMID: 27121329); c.611A>G (PMID: 30050108); p.S70del (PMID: 28982351) (PM3_strong). Computational evidence supports a deleterious effect (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong, PP3. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 147 of the PAH protein (p.Pro147Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 26322415, 27121329, 31355225). ClinVar contains an entry for this variant (Variation ID: 102670). 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: 10598814, 27121329). 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. - |
not provided Pathogenic:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 16, 2017 | - - |
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