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]

Link to SEPIO compliant JSON-LD document

CA386304277

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 644dc10b-d8fe-4691-a94b-a62d358ef02b

HGVS expressions

NM_001354304.2:c.169-1G>A

NM_000277.1:c.169-1G>A

NM_000277.2:c.169-1G>A

NM_001354304.1:c.169-1G>A

NM_000277.3:c.169-1G>A

ENST00000307000.7:c.154-1G>A

ENST00000546844.1:c.169-1G>A

ENST00000548677.2:n.256-1G>A

ENST00000548928.1:n.91-1G>A

ENST00000549111.5:n.265-1G>A

ENST00000550978.6:n.153-1G>A

ENST00000551337.5:c.169-1G>A

ENST00000551988.5:n.258-1G>A

ENST00000553106.5:c.169-1G>A

ENST00000635500.1:n.137-1G>A

NC_000012.12:g.102894919C>T

CM000674.2:g.102894919C>T

NC_000012.11:g.103288697C>T

CM000674.1:g.103288697C>T

NC_000012.10:g.101812827C>T

NG_008690.1:g.27684G>A

NG_008690.2:g.68492G>A

Pathogenic

PP4 PVS1 PM2 PM3

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

This c.169-1G>A (aka IVS2-1G>A) variant in PAH has been observed in at least two patients with PAH deficiency (PMID: 18294361 and 30159852) in trans with pathogenic variant c.168+5G>C. One patient was homozygous for this variant (PMID: 30159852). This variant is absent in controls from population databases. This variant in the -1 splice acceptor site of intron 2 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. This variant breaks the splice site in intron 2 according to computational models. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, and PP4.

PP4

This variant is observed in at least two patients, one with classical PKU and the other with unspecified Phe levels. BH4 deficiency was not ruled out in this study. PMID: 30159852

PubMed:30159852

PVS1

This variant in the -1 splice acceptor site of IVS2 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 IVS2 according to Splice AI (1- splice altering) and TraP (0.558, >99%ile, probably damaging).

PM2

This variant is absent in controls in gnomAD, ExAC, and 1000 Genomes population databases.

PM3

[c.169-1G>A; c.168+5G>C] and [c.169-1G>A; c.169-1G>A]. Segregation analysis was done. PMID: 30159852

Approved on: 2020-10-15

Published on: 2020-10-15

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