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

CA645584081

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 30d2b670-3555-4ff4-8b51-001ee0d9d0d3

HGVS expressions

NM_001354304.2:c.969+4A>T

NC_000012.12:g.102846891T>A

CM000674.2:g.102846891T>A

NC_000012.11:g.103240669T>A

CM000674.1:g.103240669T>A

NC_000012.10:g.101764799T>A

NG_008690.1:g.75712A>T

NG_008690.2:g.116520A>T

ENST00000307000.7:c.954+4A>T

ENST00000553106.5:c.969+4A>T

NM_000277.1:c.969+4A>T

NM_000277.2:c.969+4A>T

NM_001354304.1:c.969+4A>T

NM_000277.3:c.969+4A>T

Uncertain Significance

PP3 PP4_Moderate PM2

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.969+4A>T PAH variant has been reported in 1 Northwest Chinese patient with PAH deficiency (Phe ≥ 1200 μmol/L) (PMID: 30747360). A defect in BH4 metabolism was excluded through a BH4 loading test, urinary pterin analysis, and DHPR activity assay. This variant is absent from population databases gnomAD, 1000 Genomes and ESP. Splicing prediction algorithms predict this variant to be probably damaging. In summary, this variant meets criteria to be classified as a variant of uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_moderate, PP3.

PP3

According to splicing prediction algorithms, (Splice AI score = 0.74, splice-altering; TrAP score = 0.97 < 99.9th percentile, probably damaging) predict this intronic variant to be splice-altering.

PP4_Moderate

Detected in 1 patient with PAH deficiency (Phe ≥ 1200 μmol/L). Patients with BH4 cofactor deficiency were excluded through a BH4 loading test, urinary pterin analysis, and DHPR activity assay. PMID: 30747360

PM2

This variant is absent from population databases gnomAD, 1000 Genomes and ESP.

Approved on: 2020-12-11

Published on: 2021-03-03

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