rs62507262
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS3_SupportingPM2PP4_ModeratePP3PM3_Strong
This summary comes from the ClinGen Evidence Repository: The c.833C>T (p.Thr278Ile) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency ruled out), detected with pathogenic variants: R241C (PMID:21307867); R241C, A259T (2 patients), R413P, Y356X (PMID:15503242). Functional studies show a PAH enzyme activity of 1% compared to wild type (PMID:9860305). This variant is absent in population databases. 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/CA229803/MONDO:0009861/006
Frequency
Consequence
NM_000277.3 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 | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.833C>T | p.Thr278Ile | missense_variant | 7/13 | ENST00000553106.6 | |
PAH | NM_001354304.2 | c.833C>T | p.Thr278Ile | missense_variant | 8/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.833C>T | p.Thr278Ile | missense_variant | 7/13 | 1 | NM_000277.3 | P1 | |
PAH | ENST00000307000.7 | c.818C>T | p.Thr273Ile | missense_variant | 8/14 | 5 | |||
PAH | ENST00000549247.6 | n.592C>T | non_coding_transcript_exon_variant | 1/6 | 2 | ||||
PAH | ENST00000635477.1 | upstream_gene_variant | 5 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461770Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727188
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 14, 2018 | - - |
Pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Mar 05, 2022 | The c.833C>T (p.Thr278Ile) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency ruled out), detected with pathogenic variants: R241C (PMID: 21307867); R241C, A259T (2 patients), R413P, Y356X (PMID: 15503242). Functional studies show a PAH enzyme activity of 1% compared to wild type (PMID: 9860305). This variant is absent in population databases. 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 | Invitae | Apr 07, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PAH function (PMID: 9860305). 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. ClinVar contains an entry for this variant (Variation ID: 102863). This missense change has been observed in individual(s) with PAH-related conditions (PMID: 9860305, 15503242, 18985011, 23271928). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 278 of the PAH protein (p.Thr278Ile). - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 28, 2023 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 16, 2020 | - - |
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