chr12-102852858-G-C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000277.3(PAH):c.799C>G(p.Gln267Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q267H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000277.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.799C>G | p.Gln267Glu | missense_variant | 7/13 | ENST00000553106.6 | |
PAH | NM_001354304.2 | c.799C>G | p.Gln267Glu | missense_variant | 8/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.799C>G | p.Gln267Glu | missense_variant | 7/13 | 1 | NM_000277.3 | P1 | |
PAH | ENST00000307000.7 | c.784C>G | p.Gln262Glu | missense_variant | 8/14 | 5 | |||
PAH | ENST00000549247.6 | n.558C>G | 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:1
Pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Dec 10, 2018 | The c.799C>G (p.Gln267Glu) variant in PAH was reported in 2 Chinese PKU patients. BH4 deficiencies not completely ruled out. (PMID: 26600521) This variant was detected with known pathogenic variants p.R111X (PMID: 16256386), and D101N (not in ClinVar, PMID: 26600521). It is absent from ExAC, gnomAD, 1000G, and ESP. This variant is predicted deleterious in SIFT, Polyphen2, MutationTaster, and REVEL=0.935. This variant was expressed in e. coli using a rat Q267E mutant. It has 11% activity of wt. based on duplicate determinations of a single clone. (PMID: 7914195). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PS3, PP3, PP4. - |
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