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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CA16020922

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 75421939-afbe-47f8-b317-d3847d450e4e

Approved on: 2020-03-16

Published on: 2020-03-16

HGVS expressions

NM_000277.1:c.1043T>C

NC_000012.12:g.102844358A>G

CM000674.2:g.102844358A>G

NC_000012.11:g.103238136A>G

CM000674.1:g.103238136A>G

NC_000012.10:g.101762266A>G

NG_008690.1:g.78245T>C

NG_008690.2:g.119053T>C

NM_000277.2:c.1043T>C

NM_001354304.1:c.1043T>C

NM_000277.3:c.1043T>C

NM_001354304.2:c.1043T>C

ENST00000307000.7:c.1028T>C

ENST00000549247.6:n.802T>C

ENST00000551114.2:n.705T>C

ENST00000553106.5:c.1043T>C

ENST00000635477.1:n.147T>C

ENST00000635528.1:n.558T>C

Likely Pathogenic

PP3 PM5 PP4_Moderate 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.1043T>C (p.Leu348Pro) variant in PAH has been reported in a Chinese patient with PAH deficiency (BH4 deficiency excluded) (PMID: 23932990) This variant is absent from population databases. A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.981. Another missense change at the same amino acid is pathogenic: p.Leu348Val Pathogenic by 7 submitters. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM5, PP3.

PP3

Predicted deleterious in SIFT, PolyPhen2, MutationTaster. REVEL=0.981

PM5

p.Leu348Val Pathogenic 7 submitters

PP4_Moderate

PMID 23932990: In all patients, hyperphenylalaninemia (HPA) had been detected by either national screening or presence of neurological deterioration at elder age with a plasma phenylalanine (Phe) cut-off level of 120 μmol/L. A defect in the synthesis or recycling of tetrahydrobiopterin was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes.

PMID 23932990: 338 unrelated Chinese patients with two presumably causative alterations in the Pah gene from January 2006 through December 2012 were recorded in our database. In all patients, hyperphenylalaninemia (HPA) had been detected by either national screening (57.10%, 193/338) or presence of neurological deterioration at elder age (42.90%, 145/338) with a plasma phenylalanine (Phe) cut-off level of 120 μmol/L. A defect in the synthesis or recycling of tetrahydrobiopterin was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes. Patients were classified as classic PKU (Phe, more than 1200 μmol/L), moderate PKU (Phe, 900 to 1200 μmol/L), mild PKU (Phe, 600 to 900 μmol/L) and MHP who keeps their Phe levels below 600 μmol/L on a free diet. Appendix A: as unclassified patient. PubMed:23932990

PM2

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

Curation History

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