rs762949770
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP4PM2_SupportingPVS1
This summary comes from the ClinGen Evidence Repository: The NM_000277.3(PAH):c.226G>T (p.Glu76Ter) is a nonsense variant in exon 3/13 of PAH, and is predicted to result in PTC with removal of >10% of the protein and NMD (PVS1). The variant is absent from population databases, including gnomAD, ExAC, 1000 Genomes, or ESP (PM2_supporting). The variant has been previously reported in a patient with classic PKU (plasma Phe >1200 uM) (PMID:17096675) with BH4 deficiency not noted to have been formally excluded (PP4), in cis with the c.1089delG variant (ClinVar Pathogenic, see ID 102518). In summary, this variant meets criteria to be classified as Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2_supporting, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16020752/MONDO:0009861/006
Frequency
Consequence
NM_000277.3 stop_gained
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.226G>T | p.Glu76Ter | stop_gained | 3/13 | ENST00000553106.6 | |
LOC124902999 | XR_007063428.1 | n.863-9837C>A | intron_variant, non_coding_transcript_variant | ||||
PAH | NM_001354304.2 | c.226G>T | p.Glu76Ter | stop_gained | 4/14 | ||
PAH | XM_017019370.2 | c.226G>T | p.Glu76Ter | stop_gained | 3/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.226G>T | p.Glu76Ter | stop_gained | 3/13 | 1 | NM_000277.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461610Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 727122
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:2
Pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Oct 15, 2023 | The NM_000277.3(PAH):c.226G>T (p.Glu76Ter) is a nonsense variant in exon 3/13 of PAH, and is predicted to result in PTC with removal of >10% of the protein and NMD (PVS1). The variant is absent from population databases, including gnomAD, ExAC, 1000 Genomes, or ESP (PM2_supporting). The variant has been previously reported in a patient with classic PKU (plasma Phe >1200 uM) (PMID: 17096675) with BH4 deficiency not noted to have been formally excluded (PP4), in cis with the c.1089delG variant (ClinVar Pathogenic, see ID 102518). In summary, this variant meets criteria to be classified as Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2_supporting, PP4. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 14, 2016 | Variant summary: The PAH c.226G>T (p.Glu76X) variant results in a premature termination codon, predicted to cause a truncated or absent PAH protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant is absent in 121374 control chromosomes and has been reported in one HPA patient with c.1089delG in cis (Daniele_2006). c.1089delG has been reported as a frequent pathogenic variant in PKU and HPA patients. No patient with c.226G>T in separation has been reported. Taken together, this variant is classified as likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at