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

CA16020929

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 550e95f9-0dde-4ec8-9629-25a63cbf16ff

HGVS expressions

NM_000277.3:c.1066-1G>C

NC_000012.12:g.102843780C>G

CM000674.2:g.102843780C>G

NC_000012.11:g.103237558C>G

CM000674.1:g.103237558C>G

NC_000012.10:g.101761688C>G

NG_008690.1:g.78823G>C

NG_008690.2:g.119631G>C

NM_000277.1:c.1066-1G>C

NM_000277.2:c.1066-1G>C

NM_001354304.1:c.1066-1G>C

ENST00000307000.7:c.1051-1G>C

ENST00000549247.6:n.825-1G>C

ENST00000551114.2:n.728-1G>C

ENST00000553106.5:c.1066-1G>C

ENST00000635477.1:n.170-1G>C

ENST00000635528.1:n.581-1G>C

Pathogenic

PP4_Moderate PVS1 PM2

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

This c.1066-1G>C (IVS10-1G>C) variant in PAH was reported in one Chinese patient with PAH deficiency (PMID: 26503515). DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia. This variant is absent from the population databases ExAC and gnomAD. This variant in the -1 splice acceptor site results in exon skipping. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4_moderate.

PP4_Moderate

This variant was documented once in a Southern Chinese patient diagnosed with PAH deficiency (PMID: 26503515).

This variant was documented once in a Southern Chinese patient diagnosed with PKU (PMID: 26503515). The patient was a compound heterozygote for the variant, however the 2nd allele was not specified. Subjects in this study were diagnosed through neonatal screening program or by clinical presentation. Phenylalanine plasma concentrations >120 µmol/L were reported for all subjects. Tetrahydrobiopterin (BH4) deficiency was excluded through a BH4 loading test, urinary pterin analysis, DHPR activity assay. PubMed:26503515

PVS1

This variant in the -1 splice acceptor site results in exon skipping. The variant disrupts the reading frame and is predicted to undergo nonsense mediated decay (NMD). This variant breaks the splice site according to HSF (-35.29%) and MaxEnt (-254.75%).

PM2

Absent from population databases gnomAD and ExAC.

Approved on: 2019-10-18

Published on: 2019-10-18

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