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

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

CA229700

102791 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

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

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

NM_000277.3(PAH):c.704A>C (p.Gln235Pro)

Uncertain Significance

PP4 PP3 PM3_Supporting PM2

PS1 PM5

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

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, detected with pathogenic variant c.442-1G>A (PMID: 16256386) This variant is absent in population databases. A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.947. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3_supporting, PP3, PP4.

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

PP3

Predicted deleterious in SIFT, Polyphen2, MutationTaster. REVEL=0.947

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

PM2

Absent from ExAC, gnomAD, 1000G, ESP

PS1

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

PM5

Only variant in this codon in ClinVar

Approved on: 2020-11-09

Published on: 2022-02-20

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