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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CA16020779

619155 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 6628a148-458a-49f0-bb4f-f4d481b62a08

Approved on: 2018-12-10

Published on: 2019-04-06

HGVS expressions

NM_000277.1:c.362T>C

NC_000012.12:g.102877541A>G

CM000674.2:g.102877541A>G

NC_000012.11:g.103271319A>G

CM000674.1:g.103271319A>G

NC_000012.10:g.101795449A>G

NG_008690.1:g.45062T>C

NG_008690.2:g.85870T>C

NM_000277.2:c.362T>C

NM_001354304.1:c.362T>C

NM_000277.3:c.362T>C

ENST00000307000.7:c.347T>C

ENST00000549111.5:n.458T>C

ENST00000550978.6:n.346T>C

ENST00000551337.5:c.362T>C

ENST00000551988.5:n.451T>C

ENST00000553106.5:c.362T>C

Uncertain Significance

PP3 PM2 PP4_Moderate

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.362T>C (p.Phe121Ser) variant in PAH is reported in 1 patient with hyperphenylalaninemia. A BH4 metabolism defect was excluded. (PMID: 26701937) This variant is absent from ExAC, gnomAD, 1000G, and ESP. It is predicted deleterious in SIFT, Polyphen2, MutationTaster, and REVEL=0.977. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PP3.

PP3

Predicted deleterious in SIFT, Polyphen2, MutationTaster. REVEL=0.977.

PM2

Absent from ExAC, gnomAD, 1000G, ESP

PP4_Moderate

F121S detected in 1 HPA patient. BH4 metabolism defect was excluded. PMID: 26701937

HPA patients who were under age four at the time treatment was initiated were included in the study. All were diagnosed during routine neonatal screening. The possible presence of a BH4 metabolism defect was excluded in all patients. F121S was detected on 1 allele. PubMed:26701937

PM5

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

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