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]

Variant: NM_000277.3(PAH):c.563G>A (p.Gly188Asp)

CA229628

102738 (ClinVar)

Gene: PAH (HGNC:5053)

Condition: phenylketonuria (MONDO:0009861)

Inheritance Mode: Autosomal recessive inheritance

UUID: 1ebfcbe1-94c5-44ac-917b-3bb6d1edebc5

Approved on: 2019-11-18

Published on: 2021-04-09

HGVS expressions

NM_000277.3(PAH):c.563G>A (p.Gly188Asp)

NM_000277.3:c.563G>A

NC_000012.12:g.102855279C>T

CM000674.2:g.102855279C>T

NC_000012.11:g.103249057C>T

CM000674.1:g.103249057C>T

NC_000012.10:g.101773187C>T

NG_008690.1:g.67324G>A

NG_008690.2:g.108132G>A

ENST00000307000.7:c.548G>A

ENST00000553106.5:c.563G>A

NM_000277.1:c.563G>A

NM_000277.2:c.563G>A

NM_001354304.1:c.563G>A

NM_001354304.2:c.563G>A

Likely Pathogenic

PP4_Moderate PP3 PM2 PM3

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.563G>A (p.Gly188Asp) variant in PAH has been reported in 3 affected individuals (BH4 deficiency excluded). (PP4_Moderate; PMID: 23430918, 26503515, 22526846). This variant is absent in population databases (PM2). This variant was detected with pathogenic variants p.F55fs (parental analysis not reported, PMID: 22526846) and p.R243Q (in trans, PMID: 26322415; PM3). Computational evidence support 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 in a French patient with PKU (1383 pre-treatment); BH4 assessment not reported. PMID: 23430918. Detected in a Chinese patient with PKU; Dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading were assessed. PMID: 26503515. Detected in an Austrian patient with PKU PMID: 22526846

PP3

Deleterious effect predicted in SIFT, PolyPhen2, MutationTaster. REVEL=0.84.

PM2

Absent from controls in ExAC, gnomAD, 1000 Genomes, ESP

PM3

detected with p.F55fs (P by 4 submitters, LP by 1 submitter), parental analysis not reported, PMID: 22526846. Detected in trans with p.R243Q (P by 8 submitters) PMID: 26322415

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.