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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CA16020953

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 2060c1fe-a83b-4de2-8a05-ef5de2180654

HGVS expressions

NM_001354304.2:c.1161C>A

NM_000277.1:c.1161C>A

NM_000277.2:c.1161C>A

NM_001354304.1:c.1161C>A

NM_000277.3:c.1161C>A

ENST00000307000.7:c.1146C>A

ENST00000549247.6:n.920C>A

ENST00000551114.2:n.823C>A

ENST00000553106.5:c.1161C>A

ENST00000635477.1:n.265C>A

ENST00000635528.1:n.676C>A

NC_000012.12:g.102843684G>T

CM000674.2:g.102843684G>T

NC_000012.11:g.103237462G>T

CM000674.1:g.103237462G>T

NC_000012.10:g.101761592G>T

NG_008690.1:g.78919C>A

NG_008690.2:g.119727C>A

Pathogenic

PP4_Moderate PM3 PVS1

PM2

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

Variant c.1161C>A (p.Tyr387Ter) in PAH was documented 2 times in European patients with classic phenylketonuria (PMID: 16601866, 23764561)(PP4-moderate). This is a nonsense variant in exon 11 out of 13 coding exons, predicted to undergo nonsense mediated mRNA decay, as it is not located in the 3’-most exon or the 3’-most 50 bp of the penultimate exon. The exon is present in biologically-relevant transcripts (PVS1). This variant was detected in trans with pathogenic variant p.P281L (PMID:16601866, 23764561) (PM3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied:PVS1, PM3, PP4-Moderate.

PP4_Moderate

Variant p.Y387X was documented 1 time in a patient with classic phenylketonuria and 1 time in Slovakia in a patient with classic phenylketonuria (PMID: 16601866, 23764561). A defect in the synthesis or recycling of tetrahy- drobiopterin was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes.

PubMed:23764561

PubMed:16601866

PM3

This variant was detected in trans with pathogenic variant in 2 classical PKU patients: Ex5del4232ins268, p.P281L (Likely Pathogenic 11 reports) (PMID:16601866, 23764561). All the mutations identified were confirmed by analysing parental DNA.

PVS1

This is a nonsense variant in exon 11 out of 13 coding exons. The variant is predicted to undergo nonsense mediated mRNA decay (NMD), as it is not located in the 3’-most exon or the 3’-most 50 bp of the penultimate exon. The exon is present in biologically-relevant transcripts.

PM2

Variant is identified in 1/3476 European (Finnish) alleles in gnomAD. The allele frequency is 0.00029. The PM2 threshold set by the PAH Variant Curation Expert Panel (VCEP) is 0.0002.

Approved on: 2020-05-08

Published on: 2020-05-08

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