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)

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CA229628

102738 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

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

Approved on: 2019-11-18

Published on: 2021-04-09

HGVS expressions

NM_000277.3:c.563G>A

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

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 PM3 PM2 PP3

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

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

PM2

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

PP3

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

Curation History

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