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_001354304.2:c.1194A>C

CA16020959

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 8e80b0da-26d5-4179-a9b0-4413188e96ea

HGVS expressions

NM_001354304.2:c.1194A>C

NC_000012.12:g.102843651T>G

CM000674.2:g.102843651T>G

NC_000012.11:g.103237429T>G

CM000674.1:g.103237429T>G

NC_000012.10:g.101761559T>G

NG_008690.1:g.78952A>C

NG_008690.2:g.119760A>C

ENST00000553106.6:c.1194A>C

ENST00000307000.7:c.1179A>C

ENST00000549247.6:n.953A>C

ENST00000551114.2:n.856A>C

ENST00000553106.5:c.1194A>C

ENST00000635477.1:n.298A>C

ENST00000635528.1:n.709A>C

NM_000277.1:c.1194A>C

NM_000277.2:c.1194A>C

NM_001354304.1:c.1194A>C

NM_000277.3:c.1194A>C

Uncertain Significance

PP4 PP3 PM2

PS3 PM3

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

Thec.1194A>C (p.Lys398Asn) PAH variant has been reported in at least on mild HPA probrand (PMID: 17096675), having a compound heterozygous genotype with c.442-5C>G. This variant is absent from population databases, including gnomAD, ExAC, 1000 Genomes, or ESP. It is a missense variant predicted deleterious by SIFT (damaging), Polyphen (probably damaging) and MutationTaster (disease causing), with a REVEL score of 0.899. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3, PP4.

PP4

One proband with this variant in PMID: 17096675 has mild HPA (Phe between 120 and 600 μM).

PP3

This variant is predicted deleterious by SIFT (damaging), Polyphen (probably damaging) and MutationTaster (disease causing), and has a REVEL score of 0.899.

PM2

This variant is absent from population databases, including gnomAD, ExAC, 1000 Genomes, or ESP.

PS3

Transient expression of the Lys398Asn PAH variant in HEK293 cells yielded activity of 55% compared to wild-type. This does not meet the threshold of <50%.

PM3

One compound heterozygous proband has been reported in PMID: 17096675 and PMID: 18346471; the second variant is c.442-5C>G (ClinVar 102677) which has been classified as VUS by the ClinGen Phenylketonuria VCEP. These variants were not reported to have confirmation of trans phase.

Approved on: 2020-05-08

Published on: 2022-02-20

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