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.912+2T>C

Curation Version - 1.0
Curation History
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CA267684

120292 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 301e2d2c-9d56-450b-8518-43322c37c503

Approved on: 2019-09-29

Published on: 2019-10-02

HGVS expressions

NM_000277.2:c.912+2T>C

NM_000277.2(PAH):c.912+2T>C

NC_000012.12:g.102851685A>G

CM000674.2:g.102851685A>G

NC_000012.11:g.103245463A>G

CM000674.1:g.103245463A>G

NC_000012.10:g.101769593A>G

NG_008690.1:g.70918T>C

NG_008690.2:g.111726T>C

NM_000277.1:c.912+2T>C

NM_001354304.1:c.912+2T>C

NM_000277.3:c.912+2T>C

ENST00000307000.7:c.897+2T>C

ENST00000549247.6:n.671+2T>C

ENST00000551114.2:n.574+2T>C

ENST00000553106.5:c.912+2T>C

ENST00000635477.1:n.73+2T>C

Pathogenic

PM2 PVS1 PM3 PP4

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.912+2T>C variant in PAH is reported Likely Pathogenic in ClinVar (see variant ID 120292) by one laboratory, which states that it was found in a PKU patient but does not provide further information to support their classification. With respect to the published literature, it has been previously reported in one Croatian proband with “severe” PKU (defined as serum Phe levels >1200); BH4 deficiency does not appear to have been formally excluded (PMID: 12655552) (PP4). The variant was found as a single (heterozygous) variant with the known pathogenic p.R408W allele (see ClinVar variant ID 577) (PM3); phase was confirmed via parental testing. The variant is a null variant (canonical +2 splice site) in a gene 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 (PVS1). It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4.

PM2

It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2).

PVS1

The variant is a null variant (canonical +/- 1 or 2 splice sites) in a gene 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 (PVS1).

PM3

With respect to the published literature, it has been previously reported in one Croatian proband with “severe” PKU (defined as serum Phe levels >1200); BH4 deficiency does not appear to have been formally excluded (PMID: 12655552) (PP4). The variant was found as a single (heterozygous) variant with the known pathogenic p.R408W allele (see ClinVar variant ID 577) (PM3); phase was confirmed via parental testing.

PP4

Curation History

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