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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CA16020938

619153 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 091220fb-ed36-4e4d-bcd9-aa8cf3d9d1b0

HGVS expressions

NM_000277.1:c.1099C>G

NC_000012.12:g.102843746G>C

CM000674.2:g.102843746G>C

NC_000012.11:g.103237524G>C

CM000674.1:g.103237524G>C

NC_000012.10:g.101761654G>C

NG_008690.1:g.78857C>G

NG_008690.2:g.119665C>G

NM_000277.2:c.1099C>G

NM_001354304.1:c.1099C>G

NM_000277.3:c.1099C>G

ENST00000307000.7:c.1084C>G

ENST00000549247.6:n.858C>G

ENST00000551114.2:n.761C>G

ENST00000553106.5:c.1099C>G

ENST00000635477.1:n.203C>G

ENST00000635528.1:n.614C>G

Uncertain Significance

PM2 PP4_Moderate

PP3 PM3

Evidence Links 3

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1099C>G (p.Leu367Val) variant in PAH is reported in 2 unrelated patients with PKU (from Italy and China). BH4 deficiencies were assessed in the Chinese patient. (PMID: 10693064, 26503515) It was detected in the Chinese patient with c.1174T>A (p.F392I) (not in ClinVar). This variant is absent in population databases. Computational evidence is conflicting. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2.

PM2

Absent from Controls.

PP4_Moderate

Seen in two patients with PKU (Italy and China). BH4 deficiencies were assessed in the Chinese patient. PMID: 10693064, 26503515

Seen in an Italian Patient with PKU. PubMed:10693064

Seen in a patient with PKU. These patients were diagnosed at birth either through a neonatal screening program or based on 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 models. Deleterious by SIFT and Muttaster. Benign by Polyphen.

PM3

Detected with c.1174T>A p.F392I (not in ClinVar)

Patient genoype: c.[1099C>G];[1174T>A] p.[L367V ];[F392I] (not in ClinVar) PubMed:26322415

Approved on: 2018-12-09

Published on: 2019-04-06

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