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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CA16020966

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: e504fdb0-7c96-4ede-9084-2996ee65c87b

Approved on: 2019-11-05

Published on: 2019-11-06

HGVS expressions

NM_000277.3:c.1200-1G>C

NC_000012.12:g.102840516C>G

CM000674.2:g.102840516C>G

NC_000012.11:g.103234294C>G

CM000674.1:g.103234294C>G

NC_000012.10:g.101758424C>G

NG_008690.1:g.82087G>C

NG_008690.2:g.122895G>C

NM_000277.1:c.1200-1G>C

NM_000277.2:c.1200-1G>C

NM_001354304.1:c.1200-1G>C

ENST00000307000.7:c.1185-1G>C

ENST00000549247.6:n.959-1G>C

ENST00000551114.2:n.862-1G>C

ENST00000553106.5:c.1200-1G>C

ENST00000635477.1:n.304-1G>C

ENST00000635528.1:n.715-1G>C

Pathogenic

PP4_Moderate PM3_Supporting PVS1 PM2

Evidence Links 4

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

This c.1200-1G>C (IVS11-1G>C) variant in PAH was reported in 5 patients with PAH deficiency (PMID: 26503515, 30747360, 31102715). This variant was also documented in one Thai patient diagnosed with Classic PKU with the pathogenic variant c.611A>G (PMID: 28915855). This variant is absent from the population databases ExAC and gnomAD. This variant in the -1 splice acceptor site results in exon skipping, which disrupts the reading frame. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1_very strong, PM2, PP4_moderate, PM3_supporting.

PP4_Moderate

This variant was documented in 2 patients with mild hyperphenylalaninemia and 3 patients with PAH deficiency (PMID: 26503515, 30747360, 31102715).

This variant was documented three times in Southern Chinese patients with PAH deficiency (PMID: 26503515). It was not specified whether patient genotypes were homozygous or compound heterozygous for the variant. 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

This variant was documented in a Chinese patient diagnosed with mild hyperphenylalaninemia (120 < Phe < 600 μmol/L) who was compound heterozygous for the c.1200-1G>C and c.827T>C variants (PMID: 31102715). PubMed:31102715

This variant was documented in 1 patient with mild hyperphenylalaninemia. All patients were excluded from tetrahydrobiopterin deficiency through a BH4 loading test, a urinary pterin analysis, and a DHPR activity assay on dried blood spot (DBS) samples. PubMed:30747360

PM3_Supporting

This variant was documented with the pathogenic variant c.611A>G in one Thai patient diagnosed with Classic PKU (PMID: 28915855).

This variant was documented with the pathogenic variant c.611A>G in one Thai patient diagnosed with Classic PKU (PMID: 28915855). The patient's neonatal phenylalanine screening level was 42.6 mg/dL. The publication did not indicate whether parental analysis was performed to confirm compound heterozygosity. PubMed:28915855

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).

PM2

Absent from population databases gnomAD and ExAC.

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