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

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

CA267625

120258 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

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

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

PM2 PVS1 PP4_Moderate

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.

PM2

Absent from all population databases.

PVS1

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

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

Approved on: 2019-04-24

Published on: 2019-04-24

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