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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CA16020933

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: a93e52bd-88fe-43c5-b618-e25cef43653f

HGVS expressions

NM_001354304.2:c.1071C>A

NM_000277.1:c.1071C>A

NM_000277.2:c.1071C>A

NM_001354304.1:c.1071C>A

NM_000277.3:c.1071C>A

ENST00000307000.7:c.1056C>A

ENST00000549247.6:n.830C>A

ENST00000551114.2:n.733C>A

ENST00000553106.5:c.1071C>A

ENST00000635477.1:n.175C>A

ENST00000635528.1:n.586C>A

NC_000012.12:g.102843774G>T

CM000674.2:g.102843774G>T

NC_000012.11:g.103237552G>T

CM000674.1:g.103237552G>T

NC_000012.10:g.101761682G>T

NG_008690.1:g.78829C>A

NG_008690.2:g.119637C>A

Pathogenic

PP4_Moderate PVS1 PM2 PM3_Strong

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

This variant c.1071C>A (p.Cys357Ter) in PAH was reported with pathogenic variants p.Val399=, p.Arg243Gln and c.721C>T in 3 patients with PAH deficiency. BH4 deficiency was excluded through a BH4 loading test, urinary pterin analysis, and DHPR activity assay for 1 patient. (PMID: 28754886, 28982351, 31445982). This is a nonsense variant in exon 11 out of 13 coding exons, predicted to undergo nonsense mediated mRNA decay. The exon is present in biologically-relevant transcripts. This variant is absent in population databases. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM3 strong, PM2, PP4 moderate.

PP4_Moderate

This variant was documented in 2 patients with classic PKU (>1,200 μmol/L Phe) and 1 patient with mild PKU (360–600 μmol/L). For the mild PKU patient BH4 deficiency was excluded through a BH4 loading test, urinary pterin analysis, and DHPR activity assay. (PMID: 28754886, 28982351, 31445982)

PVS1

This is a nonsense variant in exon 11 out of 13 coding exons. The variant is predicted to undergo nonsense mediated 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. Loss of function is a known mechanism of disease: 175 pathogenic null variants were reported in ClinVar for this gene across 13 different exons, 24 of which are in exon 11.

PM2

This variant is absent from population databases gnomAD, 1000 Genomes and ESP.

PM3_Strong

This variant was detected in 2 patients with a PKU phenotype, it was not specified whether the patients genotypes were homozygous or compound heterozygous for the variant. p.Arg243Gln(P) .5pts, c.721C>T(P) .5pts, and detected in trans in 1 patient with a classic PKU phenotype p.Val399= (P) 1.0pts (PMID: 28754886, 28982351, 31445982)

Approved on: 2020-12-07

Published on: 2021-01-15

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