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.1315+2T>C

Curation Version - 1.0
Curation History
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CA229429

102588 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: d9c83133-49d7-48ae-af5f-702bc7606dad

Approved on: 2018-12-09

Published on: 2019-08-17

HGVS expressions

NM_000277.2:c.1315+2T>C

NM_000277.2(PAH):c.1315+2T>C

NC_000012.12:g.102840398A>G

CM000674.2:g.102840398A>G

NC_000012.11:g.103234176A>G

CM000674.1:g.103234176A>G

NC_000012.10:g.101758306A>G

NG_008690.1:g.82205T>C

NG_008690.2:g.123013T>C

NM_000277.1:c.1315+2T>C

NM_001354304.1:c.1315+2T>C

NM_000277.3:c.1315+2T>C

ENST00000307000.7:c.1300+2T>C

ENST00000551114.2:n.977+2T>C

ENST00000553106.5:c.1315+2T>C

ENST00000635477.1:n.419+2T>C

ENST00000635528.1:n.830+2T>C

Likely Pathogenic

PP4_Moderate PM2 PM3_Strong

PP3

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1315+2T>C variant is at the 3' canonical splice site in the penultimate exon of PAH. It is absent form population databases and has been identified in trans with pathogenic variants in three independent patients (F39del, Y414C, and R261X; PMID: 9452062; 9521426). A defect of BH4 metabolism was excluded as a cause of elevated phenylalanine in all patients. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong.

PP4_Moderate

Two patients, one in trans with Y414C (mild PKU) and one in trans with R261X (classic PKU. BH4 defect excluded in all patients. PMID: 9521426

Two patients, one in trans with Y414C (mild PKU) and one in trans with R261X (classic PKU PubMed:9521426

PM2

Absent from ExAC and gnomAD.

PM3_Strong

In trans with F39del in a single patient with PKU (PMID: 9452062) and in trans with Y414C (mild PKU) and R261X (classic PKU) (PMID: 9521426)

Found in trans with F39del in a single patient with classic PKU PubMed:9452062

Two patients, one in trans with Y414C (mild PKU) and one in trans with R261X (classic PKU PubMed:9521426

PP3

Human Splicing Finder suggests no impact on splicing. Michiels, 1998 (PMID 9452062) states this leads to termination of the protein at aa 440/453.

Curation History

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