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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CA16020948

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: bd20440e-4614-4e6e-baf6-1e69c9a1d850

Approved on: 2019-12-22

Published on: 2019-12-22

HGVS expressions

NM_000277.3:c.1146C>G

NC_000012.12:g.102843699G>C

CM000674.2:g.102843699G>C

NC_000012.11:g.103237477G>C

CM000674.1:g.103237477G>C

NC_000012.10:g.101761607G>C

NG_008690.1:g.78904C>G

NG_008690.2:g.119712C>G

NM_000277.1:c.1146C>G

NM_000277.2:c.1146C>G

NM_001354304.1:c.1146C>G

ENST00000307000.7:c.1131C>G

ENST00000549247.6:n.905C>G

ENST00000551114.2:n.808C>G

ENST00000553106.5:c.1146C>G

ENST00000635477.1:n.250C>G

ENST00000635528.1:n.661C>G

Likely Pathogenic

PM2 PM3_Supporting PS1 PP4 PP3

PS3

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1146C>G (p.Phe382Leu) variant in PAH has been reported in at least 1 individual with mild HPA (PP4; PMID: 18346471). The compound heterozygous individual also harbored the known pathogenic variant Arg252Trp (ClinVar 584) (PM3_suppporting). The c.1146C>G variant is absent in population databases (PM2). Computational prediction tools suggest that the variant may impact the protein (PP3). This variant generates the same amino acid change as c.1144T>C (p.Phe382Leu) which has been interpreted as Pathogenic by the ClinGen PAH Expert Panel (PS1). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PS1, PM2, PP4, PM3_supporting, PP3.

PM2

This variant is absent from all population cohorts in gnomAD, ExAC, 1000 Genomes, and ESP.

PM3_Supporting

At least one patient has been reported to be compound heterozygous for Phe382Leu and known pathogenic variant Arg252Trp (ClinVar 584, Pathogenic).

PS1

The variant c.1144T>C (p.Phe382Leu) generates the same amino acid change and has been provisionally interpreted as Pathogenic by the ClinGen PAH Expert Panel.

PP4

At least one mild HPA patient has been reported, however exclusion of a defect of BH4 cofactor metabolism was not reported.

PubMed:18346471

PP3

Predicted deleterious in SIFT, PolyPhen2, and Mutation Taster, REVEL = 0.776.

PS3

The Phe382Leu variant was expressed in HEK293 cells and shown to have 56% enzymatic activity compared to WT control.

The Phe382Leu variant was expressed in HEK293 cells and shown to have 56% enzymatic activity compared to WT control. This does not meet the <50% threshold for PS3. PubMed:18346471

Curation History

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