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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Variant: NM_000277.3(PAH):c.870T>G (p.His290Gln)

CA16020878

558612 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Link to MONDO

UUID: ceb0df0b-f4b8-44ee-8a55-395ed325e306

Approved on: 2019-12-02

Published on: 2021-09-19

HGVS expressions

NM_000277.3:c.870T>G

NM_000277.3(PAH):c.870T>G (p.His290Gln)

ENST00000553106.6:c.870T>G

ENST00000307000.7:c.855T>G

ENST00000549247.6:n.629T>G

ENST00000551114.2:n.532T>G

ENST00000553106.5:c.870T>G

ENST00000635477.1:n.31T>G

NM_000277.1:c.870T>G

NM_000277.2:c.870T>G

NM_001354304.1:c.870T>G

NM_001354304.2:c.870T>G

NC_000012.12:g.102851729A>C

CM000674.2:g.102851729A>C

NC_000012.11:g.103245507A>C

CM000674.1:g.103245507A>C

NC_000012.10:g.101769637A>C

NG_008690.1:g.70874T>G

NG_008690.2:g.111682T>G

Uncertain Significance

PP4 PP3 PM2 PM3_Supporting

PM5 PS3

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.870T>G (p.His290Gln) variant in PAH has been reported in one patient with classic PKU (BH4 deficiency not excluded; PP4; PMID: 26210745). It was detected with known pathogenic variant p.R261Q, but parental testing was not reported/performed. This variant is absent from 1000G, ESP, ExAC and gnomAD. A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.924. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PP3, PM3_supporting.

PP4

detected in a patient with classical PKU, BH4 deficiency not reportedly assessed.

PP3

Predicted deleterious in SIFT, PolyPhen2, MutationTaster. REVEL=0.924

PM2

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

PM3_Supporting

Detected with p.R261Q (P by 8 submitters), Parental studies not reported

PM5

p.His290Leu: LP; p.His290Arg: not provided

PS3

The His285, His290, and Glu330 in rat phenylalanine hydroxylase were mutated to glutamine, glutamate, and histidine. All of the mutant proteins had low but measurable activities for tyrosine formation and greatly decreased the affinity for iron.

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