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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CA386294521

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: bd85901e-db8a-41a6-9f31-0446df09589d

Approved on: 2020-12-07

Published on: 2021-01-15

HGVS expressions

NM_001354304.2:c.843-1G>A

NM_000277.1:c.843-1G>A

NM_000277.2:c.843-1G>A

NM_001354304.1:c.843-1G>A

NM_000277.3:c.843-1G>A

ENST00000307000.7:c.828-1G>A

ENST00000549247.6:n.602-1G>A

ENST00000551114.2:n.504G>A

ENST00000553106.5:c.843-1G>A

ENST00000635477.1:n.4-1G>A

NC_000012.12:g.102851757C>T

CM000674.2:g.102851757C>T

NC_000012.11:g.103245535C>T

CM000674.1:g.103245535C>T

NC_000012.10:g.101769665C>T

NG_008690.1:g.70846G>A

NG_008690.2:g.111654G>A

Pathogenic

PP4 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 c.843-1G>A variant in PAH was reported in trans with pathogenic variants p.S70del and p.Arg243Gln in 2 Han Chinese patients with PAH deficiency (PMID: 28982351). This variant is present in European (non-Finnish) populations at an extremely low frequency in gnomAD (MAF=0.000008827). This variant in the -1 splice acceptor site of intron 7 disrupts the reading frame and is predicted to undergo nonsense mediated decay (NMD). The exon is present in biologically-relevant transcripts. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM3 strong, PM2, PP4

PP4

Detected in 2 Han Chinese patients with PAH deficiency (2220 μmol/L Phe, 1812 μmol/L Phe). Patients with BH4 cofactor deficiency were excluded by BH4 loading. PMID: 28982351

PVS1

This variant in the -1 splice acceptor site of IVS7 results in exon skipping or use of a cryptic splice site. The variant disrupts the reading frame and is predicted to undergo nonsense mediated decay (NMD). This variant breaks the splice site in IVS7 according to Splice AI (0.83) and TraP (0.593, >97.5%ile, probably damaging).

PM2

This variant is present in European (Non-Finnish) populations an extremely low frequency in gnomAD (MAF=0.000008827).

PM3_Strong

Detected in trans in 2 patients with pathogenic PAH variants p.S70del (P) 1.0pts and p.Arg243Gln (P) 1.0pts PMID: 28982351

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