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

CA16020738

619149 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 976702ea-6fd3-46bb-b3b3-2624b3ebc581

HGVS expressions

NM_000277.1:c.184C>G

NC_000012.12:g.102894903G>C

CM000674.2:g.102894903G>C

NC_000012.11:g.103288681G>C

CM000674.1:g.103288681G>C

NC_000012.10:g.101812811G>C

NG_008690.1:g.27700C>G

NG_008690.2:g.68508C>G

NM_000277.2:c.184C>G

NM_001354304.1:c.184C>G

NM_000277.3:c.184C>G

ENST00000307000.7:c.169C>G

ENST00000546844.1:c.184C>G

ENST00000548677.2:n.271C>G

ENST00000548928.1:n.106C>G

ENST00000549111.5:n.280C>G

ENST00000550978.6:n.168C>G

ENST00000551337.5:c.184C>G

ENST00000551988.5:n.273C>G

ENST00000553106.5:c.184C>G

ENST00000635500.1:n.152C>G

Uncertain Significance

PP4_Moderate PM2

PP3 PM5

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.184C>G (p.Leu62Val) variant in PAH is reported in a Chinese PAH patient. BH4 deficiency was excluded. (PMID: 23932990) This variant is absent from ExAC, gnomAD, 1000G, and ESP. Computational evidence is conflicting. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4.

PP4_Moderate

L62V identified in Chinese PAH patient. BH4 deficiency was excluded. 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 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. L62V was identified. PubMed:23932990

PM2

Absent from ExAC, gnomAD, 1000G, ESP

PP3

Conflicting predictions of pathogenicity. SIFT:T,D; Polyphen2:B; MutationTaster:D. REVEL=0.748

PM5

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

Approved on: 2018-12-10

Published on: 2019-04-06

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