rs199475676
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM3_StrongPM2PVS1PP4_Moderate
This summary comes from the ClinGen Evidence Repository: The PAH variant c.799C>T (p.Gln267Ter) is a null variant (stop gain) located in exon number 7 of the PAH gene. Loss of function in the PAH gene is a mechanism of disease. Eleven null variants in exon 7 of the PAH gene have been reported. The mRNA transcript is predicted to undergo NMD.The variant c.799C>T (p.Gln267Ter) was reported in trans with the pathogenic PAH variant c.442-1G>A (ClinVar ID: 594) in a Chinese patient with classic PKU (Phe levels >20 mg/dl). BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes. (PMID:26322415). The PAH variant c.799C>T (p.Gln267Ter) was also reported in trans with the pathogenic PAH variant IVS10‐11G>A (ClinVar ID: 607) in a Brazilian patient with classic PKU (PMID:18798839) PM3_Strong (2.0). The variant c.799C>T (p.Gln267Ter) is absent from the gnomAD, ExAC, PAGE, and ESP population databases. In summary, this variant meets the criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3_Strong, PVS1, PP4-moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16020861/MONDO:0009861/006
Frequency
Consequence
NM_000277.3 stop_gained
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.799C>T | p.Gln267Ter | stop_gained | 7/13 | ENST00000553106.6 | |
PAH | NM_001354304.2 | c.799C>T | p.Gln267Ter | stop_gained | 8/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.799C>T | p.Gln267Ter | stop_gained | 7/13 | 1 | NM_000277.3 | P1 | |
PAH | ENST00000307000.7 | c.784C>T | p.Gln262Ter | stop_gained | 8/14 | 5 | |||
PAH | ENST00000549247.6 | n.558C>T | non_coding_transcript_exon_variant | 1/6 | 2 | ||||
PAH | ENST00000635477.1 | upstream_gene_variant | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:2
Pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | May 09, 2020 | The PAH variant c.799C>T (p.Gln267Ter) is a null variant (stop gain) located in exon number 7 of the PAH gene. Loss of function in the PAH gene is a mechanism of disease. Eleven null variants in exon 7 of the PAH gene have been reported. The mRNA transcript is predicted to undergo NMD. The variant c.799C>T (p.Gln267Ter) was reported in trans with the pathogenic PAH variant c.442-1G>A (ClinVar ID: 594) in a Chinese patient with classic PKU (Phe levels >20 mg/dl). BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes. (PMID: 26322415). The PAH variant c.799C>T (p.Gln267Ter) was also reported in trans with the pathogenic PAH variant IVS10-11G>A (ClinVar ID: 607) in a Brazilian patient with classic PKU (PMID: 18798839) PM3_Strong (2.0). The variant c.799C>T (p.Gln267Ter) is absent from the gnomAD, ExAC, PAGE, and ESP population databases. In summary, this variant meets the criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3_Strong, PVS1, PP4-moderate. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 05, 2018 | This sequence change creates a premature translational stop signal (p.Gln267*) in the PAH gene. It is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). This variant has been observed in several individuals affected with PKU (PMID: 26322415, 18798839). This variant is not present in population databases (ExAC no frequency). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at