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_000277.2(PAH):c.712A>C (p.Thr238Pro)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229705

102796 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: adefc5ed-7d59-4119-8b3d-07dcdc504c09

Approved on: 2020-10-23

Published on: 2020-10-23

HGVS expressions

NM_000277.2:c.712A>C

NM_000277.2(PAH):c.712A>C (p.Thr238Pro)

NM_000277.1:c.712A>C

NM_001354304.1:c.712A>C

NM_000277.3:c.712A>C

NM_001354304.2:c.712A>C

ENST00000307000.7:c.697A>C

ENST00000549247.6:n.471A>C

ENST00000553106.5:c.712A>C

NC_000012.12:g.102852945T>G

CM000674.2:g.102852945T>G

NC_000012.11:g.103246723T>G

CM000674.1:g.103246723T>G

NC_000012.10:g.101770853T>G

NG_008690.1:g.69658A>C

NG_008690.2:g.110466A>C

Likely Pathogenic

PP3 PP4 PM2 PM3

PM5

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.712A>C (p.Thr238Pro) variant in PAH has been reported in 2 individuals with PKU, detected with pathogenic variants p.R408W (PMID: 1363786) and p.R158Q (PMID: 11295882). This variant is absent in population databases. Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM3, PP3.

PP3

Deleterious effect predicted by SIFT, Polyphen2, MutationTaster. REVEL=0.972

PP4

T238P identified in a patient with classical PKU from West Germany/Bulgaria. BH4 deficiency not excluded. PMID: 1363786

Complete sequence analysis of 194 human phenylalanine hydroxylase genes from PKU patients originating from West Germany and Bulgaria revealed 13 different mutations within exon 7 of the gene. T238P: ACT>CCT was seen on 1 allele of a patient with classical PKU. PubMed:1363786

PM2

Absent from ExAC, gnomAD, 1000G, ESP

PM3

T238P identified with R408W, pathogenic in ClinVar. Further DNA analysis in this family traced the mutation to a haplotype 4 PKU allele and confirmed Mendelian inheritance. PMID: 1363786; R158Q, parental analysis not reported PMID: 11295882

Patient D10-3: T238P/R408W (VarID 577, Pathogenic) PubMed:1363786

PubMed:11295882

PM5

p.T238A is likely pathogenic by PAH VCEP in ClinVar (no other submitters)

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.