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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CA16020855

619159 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 5bb26a8d-7e21-4fb6-93c4-a25021d88ba1

HGVS expressions

NM_000277.1:c.773T>C

NC_000012.12:g.102852884A>G

CM000674.2:g.102852884A>G

NC_000012.11:g.103246662A>G

CM000674.1:g.103246662A>G

NC_000012.10:g.101770792A>G

NG_008690.1:g.69719T>C

NG_008690.2:g.110527T>C

NM_000277.2:c.773T>C

NM_001354304.1:c.773T>C

NM_000277.3:c.773T>C

ENST00000307000.7:c.758T>C

ENST00000549247.6:n.532T>C

ENST00000553106.5:c.773T>C

Likely Pathogenic

PM2 PM3_Supporting PP4_Moderate PP3

PM5

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.773T>C (p.Leu258Pro) variant in PAH has been reported in 3 individuals with mild PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 19786003, 23514811). This variant is absent in population databases (PM2). This variant was present in two homozygous patients. Genetic analysis in parents confirmed homozygosity. PMID: 23514811 (PM3-supporting). Computational evidence supports a deleterious effect . In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_supporting, PP3.

PM2

Absent from ExAC, gnomAD, 1000G, ESP

PM3_Supporting

p.L258P is present in two mild PKU homozygous patients. Genetic analysis in parents confirmed that the patients are homozygous. PMID: 23514811

Table 3. Patient 14. p.L258P on both alleles. p.L258P is present in two mild PKU homozygous patients. Genetic analysis in parents confirmed that the patients are homozygous. PubMed:23514811

PP4_Moderate

L258P seen in 1 patient with mild PKU. Other causes of hyperphenylananinemia had been ruled out. PMID: 19786003

Twenty-five PKU patients, from 20 unrelated families, collected over 4-year period (2003–2006) were included in the study. Patients were diagnosed after presenting clinical symptoms using plasma and urinary amino acids analysis by TLC. Positive cases were confirmed by fluorometric assay determining serum phenylalanine levels. Patients were classified as having PKU when their serum phenylalanine levels exceeded 600 μmol/L before treatment and when other causes of hyperphenylalaninemia had been ruled out. In one patient we have identified a novel mutation p.L258P (c.773T>C) in homozygous fashion associated with the milder form of the disease. PubMed:19786003

PP3

Deleterious effect predicted in SIFT, Polyphen2, MutationTaster. REVEL=0.972

PM5

No ClinVar variants in this codon

Approved on: 2018-12-10

Published on: 2019-04-05

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