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

CA16020859

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 56c4f444-b719-4f6c-ac1c-1b047860059f

HGVS expressions

NM_000277.3:c.795C>A

NC_000012.12:g.102852862G>T

CM000674.2:g.102852862G>T

NC_000012.11:g.103246640G>T

CM000674.1:g.103246640G>T

NC_000012.10:g.101770770G>T

NG_008690.1:g.69741C>A

NG_008690.2:g.110549C>A

NM_000277.1:c.795C>A

NM_000277.2:c.795C>A

NM_001354304.1:c.795C>A

NM_001354304.2:c.795C>A

ENST00000307000.7:c.780C>A

ENST00000549247.6:n.554C>A

ENST00000553106.5:c.795C>A

Pathogenic

PM2 PM3 PP4_Moderate PVS1

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The PAH variant c.795C>A (p.Cys265*) is a null variant (stop gain) located in exon number 7 of the PAH gene. The loss of function in the PAH gene is a mechanism of disease. Eleven null variants in exon 7 of the PAH gene have been reported. The mRNA transcript is predicted to undergo NMD. The PAH variant NM_001354304.2:c.795C>A (p.Cys265Ter) was detected in a Chinese patient with mild PKU (mPKU, Phe levels 10–20 mg/dl). The patient was a compound heterozygote with the pathogenic variant NM_000277.3(PAH):c.782G>A (p.Arg261Gln) (ClinVar ID: 582). All patients fulfilled the diagnostic criteria of PKU, with a blood phenylalanine concentration >2 mg/dl. BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes. All mutations identified in patients were confirmed by analyzing parental DNA. (PMID: 26322415) According to gnomAD, the PAH variant c.795C>A (p.Cys265Ter) is present at a low allele frequency in population databases, with the highest reported frequency in the European (Non-Finnish) population (0.000008798). This variant is absent from the ExAC, PAGE, and ESP population databases. In summary, this variant meets the criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PVS1, PP4_Moderate.

PM2

According to gnomAD, the PAH variant c.795C>A (p.Cys265Ter) is present at a low allele frequency in population databases, with the highest reported frequency in the European (Non-Finnish) population (0.000008798). This variant is absent from the ExAC, PAGE, and ESP population databases.

PM3

The PAH variant NM_001354304.2:c.795C>A (p.Cys265Ter) was detected in a Chinese patient with mild PKU (mPKU, Phe levels 10–20 mg/dl). The patient was a compound heterozygote with the pathogenic variant NM_000277.3(PAH):c.782G>A (p.Arg261Gln) (ClinVar ID: 582). All patients fulfilled the diagnostic criteria of PKU, with a blood phenylalanine concentration >2 mg/dl. BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes. All mutations identified in patients were confirmed by analyzing parental DNA. (PMID: 26322415) PM3: Pathogenic variant, confirmed in trans: 1

PubMed:26322415

PP4_Moderate

The PAH variant NM_001354304.2:c.795C>A (p.Cys265Ter), was detected in one patient from China with mild PKU. All patients fulfilled the diagnostic criteria of PKU, with a blood phenylalanine concentration >2 mg/dl. BH4 deficiency was excluded by the analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes. (PMID: 26322415)

PVS1

Approved on: 2020-05-09

Published on: 2020-05-09

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.