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_000277.3(PAH):c.1199+2T>G

CA386493122

557365 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: aff3b507-bd03-45fe-b78b-3ee286c8f0f4

HGVS expressions

NM_000277.3:c.1199+2T>G

NM_000277.3(PAH):c.1199+2T>G

NC_000012.12:g.102843644A>C

CM000674.2:g.102843644A>C

NC_000012.11:g.103237422A>C

CM000674.1:g.103237422A>C

NC_000012.10:g.101761552A>C

NG_008690.1:g.78959T>G

NG_008690.2:g.119767T>G

ENST00000553106.6:c.1199+2T>G

ENST00000307000.7:c.1184+2T>G

ENST00000549247.6:n.958+2T>G

ENST00000551114.2:n.861+2T>G

ENST00000553106.5:c.1199+2T>G

ENST00000635477.1:n.303+2T>G

ENST00000635528.1:n.714+2T>G

NM_000277.1:c.1199+2T>G

NM_000277.2:c.1199+2T>G

NM_001354304.1:c.1199+2T>G

NM_001354304.2:c.1199+2T>G

Likely Pathogenic

PVS1 PM2

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specification: ClinGen PAH Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1199+2T>G variant in PAH occurs within the canonical splice donor of intron 11. It is predicted to cause skipping of biologically-relevant exon 11, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism. This variant may be reported in the literature (PMID: 25863075), but is unavailable for evaluation. Sequence analysis of a PKU mouse model with this variant revealed two cryptic splice donor sites, upstream and downstream of the wild-type splice site (PMID: 11161825). This variant is absent in population databases. In summary, this variant meets criteria to be classified as Likely Pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PM2, PVS1

PVS1

This is a canonical +2 splice site variant which results in exon skipping. The variant disrupts the reading frame and is predicted to undergo nonsense mediated decay (NMD).

PM2

Absent from controls in gnomAD, ExAC, 1000 Genomes, or ESP

Approved on: 2023-03-16

Published on: 2023-03-16

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