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

CA386304179

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: d632cdc3-d490-472b-be54-f09c36ae92c2

HGVS expressions

NM_001354304.2:c.223G>C

NM_000277.1:c.223G>C

NM_000277.2:c.223G>C

NM_001354304.1:c.223G>C

NM_000277.3:c.223G>C

ENST00000307000.7:c.208G>C

ENST00000546844.1:c.223G>C

ENST00000548677.2:n.310G>C

ENST00000548928.1:n.145G>C

ENST00000549111.5:n.319G>C

ENST00000550978.6:n.207G>C

ENST00000551337.5:c.223G>C

ENST00000551988.5:n.312G>C

ENST00000553106.5:c.223G>C

NC_000012.12:g.102894864C>G

CM000674.2:g.102894864C>G

NC_000012.11:g.103288642C>G

CM000674.1:g.103288642C>G

NC_000012.10:g.101812772C>G

NG_008690.1:g.27739G>C

NG_008690.2:g.68547G>C

Likely Pathogenic

PM3 PM2 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

This c.223G>C (p.Asp75His) variant in PAH was reported in 2 patients with PAH deficiency (PMID: 29499199, 28982351) detected with the pathogenic variant p.Val399= (PMID: 28982351). DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia (PMID: 29499199). This variant is absent in population databases. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_moderate, PM3.

PM3

PM3_met: This variant was detected in trans with a pathogenic variant in 1 mild hyperphenylalaninemia (MHP) patient (PMID: 28982351). 28982351, Liu - This variant was detected in trans with the pathogenic PAH variant p.Val399= in 1 patient with mild hyperphenylalaninemia (MHP). Parental analysis was performed to confirm compound heterozygosity (Peripheral blood samples were collected from the patients and parents in each of the 643 core families; To determine sequence variability, variable sites in patient genes were aligned with the corresponding sites from the respective parents).

PM2

PM2_met: This variant is absent from population databases gnomAD and ExAC.

PP4_Moderate

PP4_moderate: This variant was documented 1 time in a patient with PAH deficiency (PMID: 29499199). 29499199, Wang - This variant was documented 1 time in a Chinese patient with mild hyperphenylalaninemia (MHP). All patients with the maximum pretreatment blood Phe concentrations above 120 μmol/L were enrolled. In addition, urinary pterin analysis using high performance liquid chromatography and a DHPR activity assay on DBS samples were also carried out to distinguish between PAH deficiency and tetrahydrobiopterin deficiency.

PubMed:28982351

PubMed:29499199

PP3

PP3_not met: Predicted to be tolerated (SIFT), possibly damaging (PolyPhen2), disease causing (MutationTaster). REVEL=0.645

PM5

PM5_not met: 3 other missense variants at this residue in ClinVar: p.Asp75Gly LP by PAH EP (expert panel), p.Asp75Val LP by PAH EP, p.Asp75Asn LP by 1 submitter.

Approved on: 2020-10-16

Published on: 2020-10-16

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.