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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CA16020736

619154 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: cfee7c8b-e49c-474a-bebe-719a67c0306e

HGVS expressions

NM_000277.1:c.176A>T

NC_000012.12:g.102894911T>A

CM000674.2:g.102894911T>A

NC_000012.11:g.103288689T>A

CM000674.1:g.103288689T>A

NC_000012.10:g.101812819T>A

NG_008690.1:g.27692A>T

NG_008690.2:g.68500A>T

NM_000277.2:c.176A>T

NM_001354304.1:c.176A>T

NM_000277.3:c.176A>T

ENST00000307000.7:c.161A>T

ENST00000546844.1:c.176A>T

ENST00000548677.2:n.263A>T

ENST00000548928.1:n.98A>T

ENST00000549111.5:n.272A>T

ENST00000550978.6:n.160A>T

ENST00000551337.5:c.176A>T

ENST00000551988.5:n.265A>T

ENST00000553106.5:c.176A>T

ENST00000635500.1:n.144A>T

Uncertain Significance

PM3 PM2 PP4

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.176A>T (p.Asp59Val) variant in PAH has been reported in an Italian patient with mild PKU (BH4 deficiency not totally excluded) with pathogenic variant p.R261Q (PP4, PM3; PMID: 25003100) This variant is absent from 1000G, ESP, ExAC and gnomAD. computational evidence is conflicting. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PP3.

PM3

Detected with R261Q, P/LP in ClinVar

Patient 8 genotype: D59V/R261Q (P/LP in ClinVar) PubMed:25003100

PM2

Absent from ExAC, gnomAD, 1000G, ESP

PP4

Identified in Italian mild PKU patient. Phe, Tyr levels, and Phe/Tyr ratio were assessed. PMID: 25003100

Seventeen subjects were sampled among the PKU patients in charge of the Department of Paediatrics and Child Neurology and Psychiatry in Rome, according to the following criteria: (a) genetically confirmed defect of PAH; (e) availability of biochemical data covering the patient’s history from the diagnosis up to the study; (f) absence of medical condition, other than PKU. Patient 5: D59V, mild PKU, Phe: 313 uM. Phe, Tyr levels, and Phe/Tyr ratio were assessed on dry blood spot on the day of neuropsychological assessment, and before T1 and T2 examinations. PubMed:25003100

PP3

Conflicting predictions of pathogenicity. SIFT:T,D; Polyphen2:B, MutationTaster:D. REVEL=0.747

Approved on: 2018-12-10

Published on: 2019-04-06

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