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]

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Variant: NM_000277.1:c.1066-3C>G

CA16020928

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 2166bbb7-300f-453a-8bca-c1dd9da021be

HGVS expressions

NM_000277.1:c.1066-3C>G

NC_000012.12:g.102843782G>C

CM000674.2:g.102843782G>C

NC_000012.11:g.103237560G>C

CM000674.1:g.103237560G>C

NC_000012.10:g.101761690G>C

NG_008690.1:g.78821C>G

NG_008690.2:g.119629C>G

ENST00000553106.6:c.1066-3C>G

ENST00000307000.7:c.1051-3C>G

ENST00000549247.6:n.825-3C>G

ENST00000551114.2:n.728-3C>G

ENST00000553106.5:c.1066-3C>G

ENST00000635477.1:n.170-3C>G

ENST00000635528.1:n.581-3C>G

NM_000277.2:c.1066-3C>G

NM_001354304.1:c.1066-3C>G

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

NM_001354304.2:c.1066-3C>G

Uncertain Significance

PP4_Moderate PP3 PM2

PM3

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1066-3C>G variant in PAH has been reported in a Korean patient with PKU (BH4 deficiency excluded, PMID: 15503242). This variant is absent from 1000G, ESP, ExAC and gnomAD. Multiple lines of computational evidence support a deleterious splicing effect (HSF, MaxENT). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PP3.

PP4_Moderate

PMID 15503242: reported in one case (Phe not specified). Urinary pterin analysis and dihydropteridine reductase (DHPR) assay were performed to exclude 6-pyruvoyltetrahydropterin synthase (PTPS) deficiencies.

PMID 15503242: reported as homozygous in one case (Phe not specified). BH4 deficiency excluded. PubMed:15503242

PP3

HSF and MaxENT: Activation of an intronic cryptic acceptor site. Potential alteration of splicing. New site +63.28, +209.35 Alteration of the WT acceptor site, most probably affecting splicing.

PM2

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

PM3

homozygous. When available, parental DNA samples were sequenced to confirm trans configurations in compound heterozygotes and to distinguish homozygosity from hemizygosity. PMID 15503242

Approved on: 2022-07-30

Published on: 2022-07-30

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