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]

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA16020865

619152 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 294f7fa4-2bba-4ea4-9bd0-32859d3e9ee3

Approved on: 2018-12-10

Published on: 2019-04-06

HGVS expressions

NM_000277.1:c.813T>G

NC_000012.12:g.102852844A>C

CM000674.2:g.102852844A>C

NC_000012.11:g.103246622A>C

CM000674.1:g.103246622A>C

NC_000012.10:g.101770752A>C

NG_008690.1:g.69759T>G

NG_008690.2:g.110567T>G

NM_000277.2:c.813T>G

NM_001354304.1:c.813T>G

NM_000277.3:c.813T>G

ENST00000307000.7:c.798T>G

ENST00000549247.6:n.572T>G

ENST00000553106.5:c.813T>G

Likely Pathogenic

PP3 PM2 PP4_Moderate PM3

PM5

Evidence Links 3

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.813T>G (p.His271Gln) variant in PAH has been reported in 3 individuals with PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 1829436, 18299955, 21307867). This variant is absent in population databases (PM2). This variant was detected with IVS10-11G>A, known pathogenic (PM3; PMID: 18299955). Computational evidence support 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, PP3.

PP3

Deleterious effect predicted in SIFT, polyphen2, MutationTaster. REVEL=0.915

PM2

Absent from ExAC, gnomAD, 1000G, ESP

PP4_Moderate

H271Q seen in 2 classic PKU patients in Israel (PMID: 1829436, 18299955) and 1 PKU patient in Japan. BH4 deficiency ruled out in Japanese patient. PMID: 21307867

Same patient as 18294361, and another patient (3 alleles): 1 patient w/classic PKU phenotype, homozygous. 2nd patient with classic PKU, IVS10-11G>A. PubMed:18299955

This study enrolled 203 Japanese residents with a serum phenylalanine level higher than 0.18mM. PAH deficiency was diagnosed at the participating institutions on the basis of absence of neurologic deterioration on a low phenylalanine diet, analysis of dihydropteridine reductase activity in red blood cells, biopterin loading test and/or pteridine analysis in urine. H271Q seen on 1 allele. PubMed:21307867

The present study is based on the 159 patients, who were Israeli citizens diagnosed through the newborn screening, either Jews, Arabs or Druze. H271Q was seen on 2 Non-Ashkenazi Jewish alleles. PubMed:18294361

PM3

detected with IVS10-11G>A, known pathogenic PMID: 18299955

Patient genotype: IVS10-11G>A/H271Q PubMed:18299955

PM5

H271L LP in ClinVar

Curation History

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.