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]

Variant: NM_000277.1:c.176A>T

CA16020736

619154 (ClinVar)

Gene: PAH (HGNC:5053)

Condition: phenylketonuria (MONDO:0009861)

Inheritance Mode: Autosomal recessive inheritance

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

Approved on: 2018-12-10

Published on: 2018-12-10

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

PP4 PM2 PM3

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.

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

PM2

Absent from ExAC, gnomAD, 1000G, ESP

PM3

Detected with R261Q, P/LP in ClinVar

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

PP3

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

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.