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_000277.3(PAH):c.1066-14C>G

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229321

102508 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 4ad11597-d41e-45b6-917a-849787630c2a

Approved on: 2020-12-11

Published on: 2021-03-03

HGVS expressions

NM_000277.3:c.1066-14C>G

NM_000277.3(PAH):c.1066-14C>G

NC_000012.12:g.102843793G>C

CM000674.2:g.102843793G>C

NC_000012.11:g.103237571G>C

CM000674.1:g.103237571G>C

NC_000012.10:g.101761701G>C

NG_008690.1:g.78810C>G

NG_008690.2:g.119618C>G

ENST00000307000.7:c.1051-14C>G

ENST00000553106.5:c.1066-14C>G

NM_000277.1:c.1066-14C>G

NM_000277.2:c.1066-14C>G

NM_001354304.1:c.1066-14C>G

NM_001354304.2:c.1066-14C>G

Likely Pathogenic

PP4_Moderate PM2 PM3_Supporting PP3

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1066-14C>G PAH variant has been reported in 1 Chinese patient with PAH deficiency (Phe =512μmol/L) detected with the pathogenic PAH variant c.1222C>T (PMID: 29499199). 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 likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_moderate, PP3, PM3_supporting.

PP4_Moderate

Detected in 1 patient with PAH deficiency (Phe =512μmol/L). Patients with BH4 cofactor deficiency were excluded through a BH4 loading test, urinary pterin analysis, and DHPR activity assay. PMID: 29499199

PM2

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

PM3_Supporting

This variant was detected with pathogenic PAH variant c.1222C>T. It was not specified whether the patient genotype was homozygous or compound heterozygous for the variant. PMID: 29499199

PP3

Splicing prediction algorithms (Splice AI score = 0.79, splice-altering; TrAP score = 0.328 < 97.5th percentile, probably damaging) predict this intronic variant to be splice-altering.

Curation History

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