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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CA16020952

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: b0a365ef-a553-4844-830e-eff0096760df

Approved on: 2020-08-10

Published on: 2021-09-26

HGVS expressions

NM_000277.1:c.1159T>G

NC_000012.12:g.102843686A>C

CM000674.2:g.102843686A>C

NC_000012.11:g.103237464A>C

CM000674.1:g.103237464A>C

NC_000012.10:g.101761594A>C

NG_008690.1:g.78917T>G

NG_008690.2:g.119725T>G

ENST00000553106.6:c.1159T>G

ENST00000307000.7:c.1144T>G

ENST00000549247.6:n.918T>G

ENST00000551114.2:n.821T>G

ENST00000553106.5:c.1159T>G

ENST00000635477.1:n.263T>G

ENST00000635528.1:n.674T>G

NM_000277.2:c.1159T>G

NM_001354304.1:c.1159T>G

NM_000277.3:c.1159T>G

NM_001354304.2:c.1159T>G

Likely Pathogenic

PM2 PP4_Moderate PM3_Strong PP3

PM5

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1159T>G (p.Tyr387Asp) variant in PAH has been reported in 3 individuals with mild and classic PKU (BH4 deficiency excluded, PMID: 17557229, 26503515), detected in trans with pathogenic variants: p.Y356*; p.R413P; p.R261Q (PMID: 30050108). This variant is absent in population databases. 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: PP4_Moderate, PM2, PM3_strong, PP3.

PM2

Absent from ExAC, gnomAD, 1000G, ESP

PP4_Moderate

Y387D found in at least 1 PKU patient (2 studies in same population may be overlapping). 1 study assessed BH4 deficiency with dihydropteridine reductase activity, urinary biopterin and neopterin ratio. PMID: 17557229, PMID: 26503515

All the exons and flaking introns of PAH gene were detected by PCR/SSCP and sequencing in 230 patients with PKU. A total of 75 different mutations were detected in 435 out of 460 mutant alleles (94.6%). Among them 3 mutations (including Y387D) have not been reported previously. Article in Chinese. PubMed:17557229

796 PKU patients from mainland China. All 13 exons and adjacent intronic regions of the PAH gene were determined by next-generation sequencing. Demographic data and biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected. Y387D found on 2 alleles. PubMed:26503515

PM3_Strong

Detected in trans with p.Y356* (P 7 submitters), p.R413P (P 6 submitters), p.R261Q (P 11 submitters). The validation tests on parents were performed using Sanger sequencing. PMID: 30050108

PP3

Predicted deleterious in SIFT, Polyphen2, MutationTaster. REVEL 0.977

PM5

Y387H has no clinical significance provided in ClinVar. PAH VCEP curated it as likely pathogenic.

Curation History

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