Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

CA16020867

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: d2e319bb-303f-4130-b819-df9e61745387

HGVS expressions

NM_000277.1:c.833C>G

NM_000277.2:c.833C>G

NM_001354304.1:c.833C>G

NM_000277.3:c.833C>G

NM_001354304.2:c.833C>G

ENST00000307000.7:c.818C>G

ENST00000549247.6:n.592C>G

ENST00000553106.5:c.833C>G

NC_000012.12:g.102852824G>C

CM000674.2:g.102852824G>C

NC_000012.11:g.103246602G>C

CM000674.1:g.103246602G>C

NC_000012.10:g.101770732G>C

NG_008690.1:g.69779C>G

NG_008690.2:g.110587C>G

Likely Pathogenic

PM3_Supporting PP4_Moderate PM5 PM2

PP3

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.833C>G (p.Thr278Ser) variant in PAH has been reported in 1 individual with mild PKU (BH4 deficiency excluded), detected with pathogenic variant IVS4-1G>A (PMID: 15503242). This variant is absent in population databases. Computational evidence is conflicting. There is another missense variant at the same amino acid that is interpreted as pathogenic (p.T278I, Variant ID:102863). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_supporting, PM5.

PM3_Supporting

detected with IVS4-1G>A (pathogenic in Clinvar). When available, parental DNA samples were sequenced to confirm trans configurations in compound heterozygotes and to distinguish homozygosity from hemizygosity. PMID: 15503242

Found in trans with IVS4 (Variant ID 594) which is pathogenic in Clinvar. PubMed:15503242

PP4_Moderate

Found in individual with classic PKU on exon 7. Urinary pterin analysis and dihydropteridine reductase (DHPR) assay were performed to exclude 6-pyruvoyltetrahydropterin synthase (PTPS) deficiencies. PMID: 15503242

Found in individual with classic PKU on exon 7. PTPS deficiency ruled out. PubMed:15503242

PM5

T278I (Variant ID:102863), interpreted as pathogenic by 2 submitters

PM2

Absent from controls in ExAC, 1000 Genomes, ESP, and gnomAD.

PP3

Tolerated in SIFT. Predicted deleterious in PolyPhen and MutationTaster.

Approved on: 2020-06-15

Published on: 2020-06-15

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.