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_000277.2(PAH):c.386A>G (p.Asp129Gly)

CA229527

102661 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 1c39ee9a-5884-4352-9d86-335d9e4491cb

Approved on: 2019-04-05

Published on: 2019-04-05

HGVS expressions

NM_000277.2:c.386A>G

NM_000277.2(PAH):c.386A>G (p.Asp129Gly)

NC_000012.12:g.102877517T>C

CM000674.2:g.102877517T>C

NC_000012.11:g.103271295T>C

CM000674.1:g.103271295T>C

NC_000012.10:g.101795425T>C

NG_008690.1:g.45086A>G

NG_008690.2:g.85894A>G

NM_000277.1:c.386A>G

NM_001354304.1:c.386A>G

NM_000277.3:c.386A>G

ENST00000307000.7:c.371A>G

ENST00000549111.5:n.482A>G

ENST00000550978.6:n.370A>G

ENST00000551337.5:c.386A>G

ENST00000551988.5:n.475A>G

ENST00000553106.5:c.386A>G

Likely Pathogenic

PP4_Moderate PP3 PM2 PM3

Evidence Links 5

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.386A>G (p.Asp129Gly) variant in PAH has been reported in multiple individuals with PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 8981952). This variant has extremely low frequency in gnomAD (MAF: 0.00001; PM2). This variant was detected in trans with known pathogenic variant c.1066-11G>A (PM3; PMID: 27121329). Computational evidence supports a deleterious effect (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3.

PP4_Moderate

Detected on 2 alleles in Spanish PKU patients, BH4 defects excluded. PMID: 8981952

Patients were considered as having PKU when the serum phenylalanine levels at diagnosis were >600 umol/liter and after exclusion of a defect in tetrahydrobiopterine metabolism. D129G detected on 2 alleles. PubMed:8981952

PP3

Deleterious effect predicted: SIFT, Polyphen2, MutationTaster, REVEL=0.984

PM2

Extremely low frequency (highest MAF in ENF gnomAD: 0.00001

PM3

Detected in trans with c.1066-11G>A PMID:27121329

Patient 5 genotype: p.D129G / p.R408W. Parental segregation not reported/performed. PubMed:23062575

Patient genotype: c.194T>C;c.386A>G / p.(Ile65Thr);p.(Asp129Gly). Parental segregation not reported/performed. PubMed:26666653

detected in the homozygous state. Parental segregation not reported/performed. PubMed:23357515

2 patients reported: 1 homozygous; patient 2: c.1066-11G4A; p.Asp129Gly. Segregation analysis was done to rule out the presence of large genomic rearrangements. PubMed:27121329

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