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.224A>T

CA16020751

619157 (ClinVar)

Gene: PAH (HGNC:5053)

Condition: phenylketonuria (MONDO:0009861)

Inheritance Mode: Autosomal recessive inheritance

UUID: a02baf54-2908-452e-974a-462fb13bcf24

Approved on: 2018-12-10

Published on: 2018-12-10

HGVS expressions

NM_000277.1:c.224A>T

NC_000012.12:g.102894863T>A

CM000674.2:g.102894863T>A

NC_000012.11:g.103288641T>A

CM000674.1:g.103288641T>A

NC_000012.10:g.101812771T>A

NG_008690.1:g.27740A>T

NG_008690.2:g.68548A>T

NM_000277.2:c.224A>T

NM_001354304.1:c.224A>T

NM_000277.3:c.224A>T

ENST00000307000.7:c.209A>T

ENST00000546844.1:c.224A>T

ENST00000548677.2:n.311A>T

ENST00000548928.1:n.146A>T

ENST00000549111.5:n.320A>T

ENST00000550978.6:n.208A>T

ENST00000551337.5:c.224A>T

ENST00000551988.5:n.313A>T

ENST00000553106.5:c.224A>T

Likely Pathogenic

PM3 PM2 PP4_Moderate

PP3 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.224A>T (p.Asp75Val) variant in PAH is reported in 1 classic PKU patient. BH4 deficiency was excluded. It was detected in trans with a known pathogenic variant, p.R413P. (PMID: 26322415) This variant is absent from ExAC, gnomAD, 1000G, and ESP.Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP4_Moderate.

PM3

Detected in trans with R413P PMID: 26322415

Patient genotype: p.[D75V];[R413P] - VarID592, Pathogenic. All mutations identified in patients were confirmed by analyzing parental DNA. PubMed:26322415

PM2

Absent from ExAC, gnomAD, 1000G, ESP

PP4_Moderate

Detected in 1 classic PKU patient. BH4 deficiency excluded. PMID: 26322415

We recruited 165 PKU patients (91 males and 74 females) from 21 newborn screening centers in China. All patients fulfilled the diagnostic criteria of PKU, with a blood phenylalanine concentration >2mg/dl. BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes. D75V was detected on 1 allele in a patient with classic PKU. PubMed:26322415

PP3

Conflicting interpretations of pathogenicity. SIFT:T,D; Polyphen2:P,B; MutationTaster:D. REVEL=0.705

PM5

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

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.