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

Criteria Specification: CSpec Registry PDF

Variant: NM_000277.2(PAH):c.533A>G (p.Glu178Gly)

CA273110

92746 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 9cbb36d6-2daf-4507-b947-3a692ec4d9e7

HGVS expressions

NM_000277.2:c.533A>G

NM_000277.2(PAH):c.533A>G (p.Glu178Gly)

NC_000012.12:g.102855309T>C

CM000674.2:g.102855309T>C

NC_000012.11:g.103249087T>C

CM000674.1:g.103249087T>C

NC_000012.10:g.101773217T>C

NG_008690.1:g.67294A>G

NG_008690.2:g.108102A>G

NM_000277.1:c.533A>G

NM_001354304.1:c.533A>G

NM_000277.3:c.533A>G

ENST00000307000.7:c.518A>G

ENST00000549111.5:n.629A>G

ENST00000551988.5:n.554A>G

ENST00000553106.5:c.533A>G

Pathogenic

PP3 PM3_Strong PM2 PP4_Moderate PS3

Expert Panel

Phenylketonuria VCEP

Evidence Links 3

Evidence submitted by expert panel

Phenylketonuria VCEP

PAH-specific ACMG/AMP criteria applied: PM2: Absent from 1000G, ESP. ExAC MAF=0.00017; PP3: Deleterious effect predicted in SIFT, Polyphen2, MutationTaster. REVEL=0.841; PS3: 39% residual phenylalanine hydroxylase activity (PMID:17935162); PP4_Moderate: Detected in 6 PKU patients. BH4 deficiency excluded. Upgraded per ClinGen PAHEP. (PMID:18294361; PMID:9634518); PM3_Strong: In trans with 3 pathogenic variants (PMID:18294361). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PS3, PP4_Moderate, PM3_Strong).

PP3

Deleterious effect predicted in SIFT, Polyphen2, MutationTaster. REVEL=0.841

PM3_Strong

In trans with 3 pathogenic variants

Detected with R408W (VarID577, Path), P281L (VarID589, Path), R261Q (VarID582, P/LP), L48S (VarID608, Path) PubMed:18294361

PM2

Absent from 1000G, ESP. ExAC MAF=0.00017

PP4_Moderate

Detected in 6 PKU patients. BH4 deficiency excluded. Upgraded per ClinGen PAHEP.

E178G detected in 1 pateint with mild hyperphenylalaninemia (HPA). PAH deficiency had been assessed after exclusion of a defect in tetrahydrobiopterin metabolism. PubMed:9634518

5 patients who are E178G compound heterozygotes (1 Moderate PKU, 1 Classic PKU, 3 Mild PKU). The patients were tested for the exclusion of lacking the cofactor BH4 for the differential characterization of the cause for the absent of PAH. PubMed:18294361

PS3

39% residual phenylalanine hydroxylase activity

39% residual phenylalanine hydroxylase activity PubMed:17935162

Approved on: 2018-08-10

Published on: 2019-04-06

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