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]

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CA481332664

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 29c30051-bb9c-4220-902f-e83b24b5fdb3

HGVS expressions

NM_001354304.2:c.441T>C

NC_000012.12:g.102877462A>G

CM000674.2:g.102877462A>G

NC_000012.11:g.103271240A>G

CM000674.1:g.103271240A>G

NC_000012.10:g.101795370A>G

NG_008690.1:g.45141T>C

NG_008690.2:g.85949T>C

NM_000277.1:c.441T>C

NM_000277.2:c.441T>C

NM_001354304.1:c.441T>C

NM_000277.3:c.441T>C

ENST00000307000.7:c.426T>C

ENST00000549111.5:n.537T>C

ENST00000550978.6:n.425T>C

ENST00000551988.5:n.530T>C

ENST00000553106.5:c.441T>C

Uncertain Significance

PM2 PP4

PM3 BP7 PP3

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.441T>C (p.Pro147=) PAH variant has been reported in 1 Chinese patient with mild hyperphenylalaninemia (PMID: 30459323) detected with the PAH variant of uncertain significance p.Arg53His. A defect in BH4 metabolism was not excluded. This variant is absent from population databases. It is a synonymous variant with conflicting predictions by splicing prediction algorithms. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4.

PM2

PM2_met: This variant is absent from population databases gnomAD and ExAC.

PP4

PP4_met: This variant was reported in 1 Chinese patient with mild hyperphenylalaninemia (PMID: 30459323). 30459323, Chen - This variant was reported in 1 Chinese patient with PAH deficiency. Phenylalanine plasma concentrations >120 μmol/L were reported for all subjects. Patients with BH4 cofactor deficiency were excluded, however, the paper did not mention urinary pterin analysis and DHPR activity as methods of exclusion.

PM3

PM3_not met: This variant was detected in trans with the PAH variant of uncertain significance p.Arg53His in one patient with mild hyperphenylalaninemia (MHP)(PMID: 30459323). Parental analysis was not performed to confirm compound heterozygosity. (The genotype was listed in the supplemental section as p.[R53H];[P147P], however, it was listed with the incorrect c., c.441A>G. This c.441A>G was not mentioned in the actual paper.)

PubMed:30459323

BP7

BP7_not met: Splicing prediction algorithms have conflicting predictions (Splice AI: benign (0.01), TraP: probably damaging (0.608), MutationTaster: likely to disturb normal splicing). The nucleotide is highly conserved.

PP3

PP3_not met: Splicing prediction algorithms have conflicting predictions (Splice AI: benign (0.01), TraP: probably damaging (0.608), MutationTaster: likely to disturb normal splicing).

Approved on: 2020-10-16

Published on: 2020-10-16

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