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_000277.2(PAH):c.704A>C (p.Gln235Pro)

Curation Version - 2.0
Curation History
JSON LD for Version 2.0

CA229700

102791 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 46b753d2-0a95-47e7-9845-a289073f7aa6

Approved on: 2024-11-17

Published on: 2024-11-18

HGVS expressions

NM_000277.2:c.704A>C

NM_000277.2(PAH):c.704A>C (p.Gln235Pro)

NC_000012.12:g.102855138T>G

CM000674.2:g.102855138T>G

NC_000012.11:g.103248916T>G

CM000674.1:g.103248916T>G

NC_000012.10:g.101773046T>G

NG_008690.1:g.67465A>C

NG_008690.2:g.108273A>C

ENST00000553106.6:c.704A>C

ENST00000307000.7:c.689A>C

ENST00000549111.5:n.800A>C

ENST00000553106.5:c.704A>C

NM_000277.1:c.704A>C

NM_001354304.1:c.704A>C

NM_000277.3:c.704A>C

NM_001354304.2:c.704A>C

Likely Pathogenic

PM3_Supporting PP3_Strong PP4 PM2_Supporting

PS1 PM5

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specification: ClinGen Phenylketonuria Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PAH Version 2.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.704A>C (p.Gln235Pro) variant in PAH has been reported in a Chinese patient with classical PKU with BH4 deficiency not excluded (PP4), detected in unknown phase with the pathogenic variant c.442-1G>A (ClinVar ID: 594, PMID: 16256386)(PM3_Supporting). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). A deleterious effect is predicted by REVEL (REVEL score 0.947) (PP3_Strong). In summary, this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: PM2_Supporting, PM3_Supporting, PP3_Strong, PP4.

PM3_Supporting

Q235P/IVS4-1G>A in 1 patient. Maternal or paternal inheritance of mutations was determined when parental DNA was available. PMID: 16256386

Q235P seen with IVS4-1G>A (VarID 594, pathogenic) in 1 patient. PubMed:16256386

PP3_Strong

REVEL=0.947

PP4

Q235P seen in 1 PKU patient. BH4 deficiency not excluded. PMID: 16256386

All exons of PAH gene in 185 unrelated patients with PKU from Northern China were studied. Q235P seen on 1 allele. PubMed:16256386

PM2_Supporting

Absent from gnomAD v4.1.0

PS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM5

c.703C>A (p.Gln235Lys) is VUS in ClinVar (ID 1384686)

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.