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.843-2A>T

CA229816

102873 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 0f80f747-69bd-4d63-9cca-27ccf00298b5

Approved on: 2019-04-09

Published on: 2019-04-09

HGVS expressions

NM_000277.2:c.843-2A>T

NM_000277.2(PAH):c.843-2A>T

NC_000012.12:g.102851758T>A

CM000674.2:g.102851758T>A

NC_000012.11:g.103245536T>A

CM000674.1:g.103245536T>A

NC_000012.10:g.101769666T>A

NG_008690.1:g.70845A>T

NG_008690.2:g.111653A>T

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

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

NM_000277.3:c.843-2A>T

ENST00000307000.7:c.828-2A>T

ENST00000549247.6:n.602-2A>T

ENST00000551114.2:n.503A>T

ENST00000553106.5:c.843-2A>T

ENST00000635477.1:n.4-2A>T

Pathogenic

PVS1 PP4 PM2

PM3

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.843-2A>T variant in PAH has been reported in 1 homozygote individual with classic PKU (PMID: 9452062). This variant disrupts the canonical splice acceptor site of intron 8 where LOF is a known mechanism of disease, exon skipping disrupts reading frame, and is predicted to undergo NMD. Coding exon 8 is present in biologically-relevant transcript. This variant is absent from population databases, including: 1000 Genomes, ESP, and gnomAD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4.

PVS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP4

reported in a patient with classic PKU, BH4 deficiency not reported/assessed. PMID: 9452062

PM2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM3

detected in the homozygous state

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