rs752792040
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP4PM2_SupportingPM3_SupportingPP3_Moderate
This summary comes from the ClinGen Evidence Repository: The c.307G>T (p.Gly103Cys) variant in PAH has been reported in 2 patients with PKU (BH4 deficiency not assessed/reported) (PP4; PMID:17502162, 24368688). It was detected in unknown phase with a pathogenic variant c.1066-11G>A (PMID:17502162) and a likely pathogenic variant p.Y154F (PMID:24368688). This variant has extremely low frequency in ExAC (MAF=0.00001). Computational evidence supports a deleterious effect (REVEL=0.819). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2_supporting, PM3_supporting, PP3_moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6748984/MONDO:0009861/006
Frequency
Consequence
NM_000277.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.307G>T | p.Gly103Cys | missense_variant | 3/13 | ENST00000553106.6 | |
LOC124902999 | XR_007063428.1 | n.863-9918C>A | intron_variant, non_coding_transcript_variant | ||||
PAH | NM_001354304.2 | c.307G>T | p.Gly103Cys | missense_variant | 4/14 | ||
PAH | XM_017019370.2 | c.307G>T | p.Gly103Cys | missense_variant | 3/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.307G>T | p.Gly103Cys | missense_variant | 3/13 | 1 | NM_000277.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152098Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461850Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3AN XY: 727222
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152098Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74296
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:1Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Jan 30, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Sep 01, 2017 | - - |
Uncertain significance, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Jul 23, 2023 | The c.307G>T (p.Gly103Cys) variant in PAH has been reported in 2 patients with PKU (BH4 deficiency not assessed/reported) (PP4; PMID: 17502162, 24368688). It was detected in unknown phase with a pathogenic variant c.1066-11G>A (PMID: 17502162) and a likely pathogenic variant p.Y154F (PMID: 24368688). This variant has extremely low frequency in ExAC (MAF=0.00001). Computational evidence supports a deleterious effect (REVEL=0.819). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2_supporting, PM3_supporting, PP3_moderate. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 12, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 103 of the PAH protein (p.Gly103Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hyperphenylalaninemia (PMID: 17502162, 24368688, 32668217; Invitae). ClinVar contains an entry for this variant (Variation ID: 553638). 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 not expected to disrupt PAH protein function with a negative predictive value of 80%. This variant disrupts the p.Gly103 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at