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]

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CA16020961

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 4abd58a1-5f5a-4c80-a66e-d1b007f1a27e

HGVS expressions

NM_001354304.2:c.1199+4A>G

NC_000012.12:g.102843642T>C

CM000674.2:g.102843642T>C

NC_000012.11:g.103237420T>C

CM000674.1:g.103237420T>C

NC_000012.10:g.101761550T>C

NG_008690.1:g.78961A>G

NG_008690.2:g.119769A>G

NM_000277.1:c.1199+4A>G

NM_000277.2:c.1199+4A>G

NM_001354304.1:c.1199+4A>G

NM_000277.3:c.1199+4A>G

ENST00000307000.7:c.1184+4A>G

ENST00000549247.6:n.958+4A>G

ENST00000551114.2:n.861+4A>G

ENST00000553106.5:c.1199+4A>G

ENST00000635477.1:n.303+4A>G

ENST00000635528.1:n.714+4A>G

Likely Pathogenic

PP3 PP4 PM3 PM2

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1199+4A>G PAH variant has been reported in 1 Danish patient with classic phenylketonuria (PMID: 26542770) detected with the pathogenic PAH variant c.1315+1G>A. A defect in BH4 metabolism was not excluded. This variant is absent from population databases. It is intronic and multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP3, PP4.

PP3

PP3_met: Predicted to be splice-altering (low) according to Splice AI (0.55) and probably damaging according to TraP (0.96).

PP4

PP4_met: This variant was reported in 1 Danish patient with classic PKU (PMID: 26542770). 26542770, Bayat - This variant was documented 1 time in a Danish patient with PAH deficiency. Pretreatment serum Phe levels were used to discriminate between the four different PKU phenotypes: classic PKU had Phe pretreatment levels>1200 μmol/l, moderate PKU 900–1200 μmol/l, mild PKU 600–900 μmol/l and MHP <600 μmol/l. BH4 deficiency was not excluded through a BH4 loading test, urinary pterin analysis and DHPR activity assay.

PM3

PM3_met: This variant was detected in trans with a pathogenic variant in 1 Danish patient with classic PKU (PMID: 26542770). 26542770, Bayat - This variant was detected in trans with the pathogenic PAH variant c.1315+1G>A in 1 Danish patient with classic PKU. Parental testing was performed to confirm compound heterozygosity.

PubMed:26542770

PM2

PM2_met: This variant is absent from population databases gnomAD and ExAC.

Approved on: 2020-10-15

Published on: 2020-10-15

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