12-102852858-G-C
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP4PP3PM3PS3
This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229769/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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.799C>G | p.Gln267Glu | missense_variant | Exon 7 of 13 | ENST00000553106.6 | NP_000268.1 | |
PAH | NM_001354304.2 | c.799C>G | p.Gln267Glu | missense_variant | Exon 8 of 14 | NP_001341233.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PAH | ENST00000553106.6 | c.799C>G | p.Gln267Glu | missense_variant | Exon 7 of 13 | 1 | NM_000277.3 | ENSP00000448059.1 | ||
PAH | ENST00000307000.7 | c.784C>G | p.Gln262Glu | missense_variant | Exon 8 of 14 | 5 | ENSP00000303500.2 | |||
PAH | ENST00000549247.6 | n.558C>G | non_coding_transcript_exon_variant | Exon 1 of 6 | 2 | |||||
PAH | ENST00000635477.1 | c.-42C>G | upstream_gene_variant | 5 | ENSP00000489230.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:1
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
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at