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]

Variant: NM_000277.2(PAH):c.1066-2A>T

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA267625

120258 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: b37dff23-d273-465e-ba1b-432ccb787caa

Approved on: 2019-04-24

Published on: 2019-04-24

HGVS expressions

NM_000277.2:c.1066-2A>T

NM_000277.2(PAH):c.1066-2A>T

NC_000012.12:g.102843781T>A

CM000674.2:g.102843781T>A

NC_000012.11:g.103237559T>A

CM000674.1:g.103237559T>A

NC_000012.10:g.101761689T>A

NG_008690.1:g.78822A>T

NG_008690.2:g.119630A>T

NM_000277.1:c.1066-2A>T

NM_001354304.1:c.1066-2A>T

NM_000277.3:c.1066-2A>T

ENST00000307000.7:c.1051-2A>T

ENST00000549247.6:n.825-2A>T

ENST00000551114.2:n.728-2A>T

ENST00000553106.5:c.1066-2A>T

ENST00000635477.1:n.170-2A>T

ENST00000635528.1:n.581-2A>T

Pathogenic

PP4_Moderate PM2 PVS1

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1066-2A>T variant in PAH is absent from all population databases, and has been identified in a patient in which a defect in BH4 metabolism was excluded as a cause of elevated phenylalanine. PMID: 21307867. It is a null variant where LOF is a known mechanism of disease, exon skipping disrupts reading frame, and is predicted to undergo NMD. Coding exon 11 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: PP4_Moderate, PVS1, PM2.

PP4_Moderate

BH4 defect excluded in all patients with pterins and DHPR activity (Okano 2011) PMID: 21307867

BH4 defect excluded in all patients with pterins and DHPR activity PubMed:21307867

PM2

Absent from all population databases.

PVS1

-2 canonical splice site. sa site for exon 12/14

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.