rs62516060
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM3_StrongPS3_SupportingPM2PP4_ModeratePP3
This summary comes from the ClinGen Evidence Repository: The c.997C>T (p.Leu333Phe) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). It was detected with multiple pathogenic variants: p.E390G (PMID:8098245); p.R261Q (PMID:21147011); p.S110L (LP by PAH VCEP, PMID:26542770). This variant is absent in population databases. In an eukaryotic expression system, the L333F mutant had 7% PAH activity as compared to wild type (PMID:10479481). Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PP4_Moderate, PM2, PP3, PS3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA114366/MONDO:0009861/006
Frequency
Consequence
ENST00000553106.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.997C>T | p.Leu333Phe | missense_variant | 10/13 | ENST00000553106.6 | NP_000268.1 | |
PAH | NM_001354304.2 | c.997C>T | p.Leu333Phe | missense_variant | 11/14 | NP_001341233.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.997C>T | p.Leu333Phe | missense_variant | 10/13 | 1 | NM_000277.3 | ENSP00000448059 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152144Hom.: 0 Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461162Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726918
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152144Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74326
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:4
Pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Mar 13, 2022 | The c.997C>T (p.Leu333Phe) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). It was detected with multiple pathogenic variants: p.E390G (PMID: 8098245); p.R261Q (PMID: 21147011); p.S110L (LP by PAH VCEP, PMID: 26542770). This variant is absent in population databases. In an eukaryotic expression system, the L333F mutant had 7% PAH activity as compared to wild type (PMID: 10479481). Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PP4_Moderate, PM2, PP3, PS3_supporting. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 02, 2024 | - - |
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 | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 27, 2023 | Variant summary: PAH c.997C>T (p.Leu333Phe) 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 was absent in 251062 control chromosomes. c.997C>T has been reported in the literature as a biallelic genotype in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example, Abadie_1993, Benit_1999, Zare-Karizi_2011, Bayat_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 7% of normal PAH enzyme activity in vitro (Benit_1999). The following publications have been ascertained in the context of this evaluation (PMID: 8098245, 26542770, 10479481, 20920871). One expert panel (ClinGen PAH Variant Curation Expert Panel) has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Hyperphenylalaninemia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1993 | - - |
not provided Other:1
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