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

PP3_Strong PM2_Supporting PM3_Supporting PP4

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.

PP3_Strong

REVEL=0.947

PM2_Supporting

Absent from gnomAD v4.1.0

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

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

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

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