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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CA16020887

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 6a4e1258-80ba-4025-a928-48cc16e67fc8

HGVS expressions

NM_000277.1:c.896T>C

NM_000277.2:c.896T>C

NM_001354304.1:c.896T>C

NM_000277.3:c.896T>C

NM_001354304.2:c.896T>C

ENST00000307000.7:c.881T>C

ENST00000549247.6:n.655T>C

ENST00000551114.2:n.558T>C

ENST00000553106.5:c.896T>C

ENST00000635477.1:n.57T>C

NC_000012.12:g.102851703A>G

CM000674.2:g.102851703A>G

NC_000012.11:g.103245481A>G

CM000674.1:g.103245481A>G

NC_000012.10:g.101769611A>G

NG_008690.1:g.70900T>C

NG_008690.2:g.111708T>C

Uncertain Significance

PP3 PM2 PM5

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.896T>C (p.Phe299Ser) variant in PAH has not been reported in a patient with PKU to our knowledge. It was noted in PMID: 9792411 but the p.Phe299Cys variant is listed as the amino acid change in the table and text, so the actual variant in the patient is unclear. This variant is absent from 1000G, ESP, ExAC and gnomAD and has an extremely low frequency in PAGE (MAF=0.00012). A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL. A different pathogenic missense change has been seen at the same amino acid (p.Phe299Cys). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM5, PP3.

PP3

Deleterious in SIFT, PolyPhen2, MutationTaster. REVEL=0.984

PM2

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

PM5

p.Phe299Cys pathogenic

Approved on: 2020-02-16

Published on: 2020-02-16

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