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.1250A>G

CA16020983

Gene: PAH (HGNC:5053)

Condition: phenylketonuria (MONDO:0009861)

Inheritance Mode: Autosomal recessive inheritance

UUID: 5f01e97d-3749-408c-a4a3-0d28f3549e87

Approved on: 2020-08-13

Published on: 2021-11-21

HGVS expressions

NM_000277.1:c.1250A>G

NC_000012.12:g.102840465T>C

CM000674.2:g.102840465T>C

NC_000012.11:g.103234243T>C

CM000674.1:g.103234243T>C

NC_000012.10:g.101758373T>C

NG_008690.1:g.82138A>G

NG_008690.2:g.122946A>G

ENST00000553106.6:c.1250A>G

ENST00000307000.7:c.1235A>G

ENST00000551114.2:n.912A>G

ENST00000553106.5:c.1250A>G

ENST00000635477.1:n.354A>G

ENST00000635528.1:n.765A>G

NM_000277.2:c.1250A>G

NM_001354304.1:c.1250A>G

NM_000277.3:c.1250A>G

NM_001354304.2:c.1250A>G

Likely Pathogenic

PP4_Moderate PP3 PM3_Supporting PM2 PM5

PS3

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1250A>G (p.Tyr417Cys) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded, PMID: 21147011). This variant has extremely low frequency in gnomAD (MAF=0.00001). It was detected with the pathogenic variant IVS10-11G>A (PMID: 28593914). Computational evidence support a deleterious effect. Another missense change at the same amino acid (p.Tyr417His) is interpreted as pathogenic. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM5, PM3_supporting, PP3.

PP4_Moderate

Y417C seen on 4 alleles of hyperphenylalaninemic patients (blood Phe <600 μmol/L). BH4 deficiency excluded (sequencing of PAH, PTS, and QDPR genes. PMID: 21147011

PP3

Predicted deleterious in SIFT, Polyphen2, MutationTaster, REVEL=0.95

PM3_Supporting

detected with IVS10-11G>A. parental analysis not reported PMID: 28593914

PM2

Absent from ExAC, 1000G, ESP. MAF=0.00001 in gnomAD (ENF)

PM5

p.Tyr417His interpreted as pathogenic by 1 submitter (GeneDx) and PAH VCEP

PS3

In vitro functional study showed Y417C mutant had 76% activity of wt PAH.

A robust LC-ESI-MSMS PAH assay for the quantification of phenylalanine and tyrosine was developed. Compared to the wild-type enzyme, the highest PAH activity at standard conditions (1 mmol/L L-Phe; 200 μmol/L BH(4)) was found for the mutant p.Y417C (76%). PubMed:22300847

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.