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

CA16020721

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: af3f49d7-dd26-4d89-93e5-b528408f5469

Approved on: 2019-03-10

Published on: 2019-08-16

HGVS expressions

NM_000277.1:c.59A>C

NC_000012.12:g.102917072T>G

CM000674.2:g.102917072T>G

NC_000012.11:g.103310850T>G

CM000674.1:g.103310850T>G

NC_000012.10:g.101834980T>G

NG_008690.1:g.5531A>C

NG_008690.2:g.46339A>C

NM_000277.2:c.59A>C

NM_001354304.1:c.59A>C

NM_000277.3:c.59A>C

ENST00000307000.7:c.-89A>C

ENST00000546844.1:c.59A>C

ENST00000547319.1:n.370A>C

ENST00000549111.5:n.155A>C

ENST00000550978.6:n.43A>C

ENST00000551337.5:c.59A>C

ENST00000551988.5:n.148A>C

ENST00000553106.5:c.59A>C

ENST00000635500.1:n.29-4174A>C

Uncertain Significance

PM2 PP4_Moderate

PP3

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

VUS: The c.59A>C (p.Q20P) variant in PAH has been reported in one Chinese patient with PKU (PMID: 26503515), however no genotype information was provided for this patient. This variant is absent from population databases, including gnomAD, ESP, and 1000 Genomes. Computation predictors are inconclusive on protein structure and function. In summary, this variant meets the criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_M.

PM2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP4_Moderate

Reported on 1 PKU allele. BH4 deficiencies assessed. PMID: 26503515

Variant reported on 1 allele. Patients diagnosed at birth either by NBS or clinical presentation. Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected. PubMed:26503515

PP3

Conflicting predictions of pathogenicity (T/B in SIFT, Polyphen2; D in MutationTaster)

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