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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CA16020737

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 6ce4710c-a4cc-4862-bb59-65b80cf308c0

Approved on: 2019-04-04

Published on: 2019-08-16

HGVS expressions

NM_000277.3:c.184del

NC_000012.12:g.102894904del

CM000674.2:g.102894904del

NC_000012.11:g.103288682del

CM000674.1:g.103288682del

NC_000012.10:g.101812812del

NG_008690.1:g.27700del

NG_008690.2:g.68508del

NM_000277.1:c.184del

NM_000277.2:c.184del

NM_001354304.1:c.184del

ENST00000307000.7:c.169del

ENST00000546844.1:c.184del

ENST00000548677.2:n.271del

ENST00000548928.1:n.106del

ENST00000549111.5:n.280del

ENST00000550978.6:n.168del

ENST00000551337.5:c.184del

ENST00000551988.5:n.273del

ENST00000553106.5:c.184del

ENST00000635500.1:n.152del

Pathogenic

PP4 PVS1 PM3 PM2

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.184delC variant in PAH has been previously reported as a heterozygous single variant in one Italian proband with mild HPA (PMID: 17096675) and in trans with the known pathogenic p.A403V allele in an Italian proband (PMID: 18346471). Of note, the two papers share the primary authors, so it is unclear whether this represents one versus two distinct patients. The variant is a 1bp deletion leading to a nonsense variant which occurs in exon 3 of 13 in the in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (see PMID: 30192042) (PVS1). It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4.

PP4

c.184delC was detected in 1 Mild HPA patient. BH4 deficiency not assessed. PMID: 17096675

We studied 126 HPA patients, identified from neonatal screening, Phe serum concentration was measured. The patients were divided into three groups: classic PKU (or HPA I) when Phe >1200 μM (>20 mg/dL); mild PKU (HPA II) when Phe was between 600 and 1200 μM (10-20 mg/dL); and mild HPA (or HPA III) when Phe was between 120 and 600 μM (2–10 mg/dL). c.184delC was detected in 0.7% of Mild HPA patients. PubMed:17096675

PVS1

The variant is a 1bp deletion leading to a nonsense variant which occurs in exon 3 of 13 in the in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (see PMID: 30192042) (PVS1).

PM3

Detected in trans with the known pathogenic p.A403V allele in an Italian proband (PMID: 18346471).

PubMed:18346471

PM2

It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2).

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