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]

Link to SEPIO compliant JSON-LD document

Variant: NM_000277.1:c.1244A>T

CA16020979

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 42d78ce7-7836-454d-925f-b7b8d391f90e

Approved on: 2020-11-09

Published on: 2022-02-20

HGVS expressions

NM_000277.1:c.1244A>T

NC_000012.12:g.102840471T>A

CM000674.2:g.102840471T>A

NC_000012.11:g.103234249T>A

CM000674.1:g.103234249T>A

NC_000012.10:g.101758379T>A

NG_008690.1:g.82132A>T

NG_008690.2:g.122940A>T

ENST00000553106.6:c.1244A>T

ENST00000307000.7:c.1229A>T

ENST00000551114.2:n.906A>T

ENST00000553106.5:c.1244A>T

ENST00000635477.1:n.348A>T

ENST00000635528.1:n.759A>T

NM_000277.2:c.1244A>T

NM_001354304.1:c.1244A>T

NM_000277.3:c.1244A>T

NM_001354304.2:c.1244A>T

Pathogenic

PP4 PP3 PM2 PM5 PM3_Strong

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1244A>T (p.Asp415Val) variant in PAH has been reported in 2 individuals with PKU, detected in trans with pathogenic variants c.1066-11G>A and c.47_48delCT (PMID: 21890392). This variant is absent in population databases. Computational prediction tools and conservation analysis support a deleterious effect. Another missense variant at the same amino acid is interpreted as pathogenic (p.Asp415Asn) In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PM5, PP3, PP4.

PP4

D415V was found in 2 PKU patients. BH4 deficiency was assessed: Phenylalanine and pterin concentrations were measured from dried blood spots using tandem mass spectrometry for phenylalanine and HPLC for pterins. All 13 exons of the PAH gene and 7 exons of the QDPR gene (encoding DHPR), plus their exon–intron boundaries were analyzed. PMID: 21890392

35 index patients identified with hyperphenylalaninemia. c.1244A>T (p.Asp415Val) was found in Cases 6 and 20. Phenylalanine and pterin concentrations were measured from dried blood spots using a routine tandem mass spectrometry method for phenylalanine and an HPLC method for pterins. All 13 exons of the PAH gene and 7 exons of the QDPR gene (encoding DHPR), plus their exon–intron boundaries were analyzed. PubMed:21890392

PP3

Deleterious effect predicted in SIFT, Polyphen2, MutationTaster, REVEL=0.954

PM2

Absent from ExAC, gnomAD, 1000G, and ESP

PM5

p.Asp415Asn Pathogenic by 9 submitters/PAH VCEP and LP by 2 submitters

PM3_Strong

Detected in trans with pathogenic variants c.1066-11G>A, c.47_48delCT. Mutations were confirmed by carrier analysis of parents and/or siblings. PMID: 21890392

D415V was found in trans with c.47_48delCT, p.S16XfsX1 (VarID 102696, Pathogenic/LP) in 1 patient and c.1066 − 11G > A (VarID 607, Pathogenic) in another patient. Mutations were confirmed by carrier analysis of parents and/or siblings. PubMed:21890392

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.