The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

  • See Evidence submitted by expert panel for details.

CA16020886

Gene: PAH
Condition: phenylketonuria
Inheritance Mode: Autosomal recessive inheritance
UUID: 0483fa48-0e0c-4847-9337-62968add6c8f
Approved on: 2019-07-07
Published on: 2019-07-07

HGVS expressions

NM_000277.3:c.890G>T
NC_000012.12:g.102851709C>A
CM000674.2:g.102851709C>A
NC_000012.11:g.103245487C>A
CM000674.1:g.103245487C>A
NC_000012.10:g.101769617C>A
NG_008690.1:g.70894G>T
NG_008690.2:g.111702G>T
NM_000277.1:c.890G>T
NM_000277.2:c.890G>T
NM_001354304.1:c.890G>T
ENST00000307000.7:c.875G>T
ENST00000549247.6:n.649G>T
ENST00000551114.2:n.552G>T
ENST00000553106.5:c.890G>T
ENST00000635477.1:n.51G>T
More

Likely Pathogenic

Met criteria codes 3
PM5 PM2 PS3
Not Met criteria codes 2
PP3 PM3

Evidence Links 3

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Phenylketonuria VCEP
The c.890G>T (p.Arg297Leu) variant in PAH has been reported in at least 1 patient with mild PKU who carried in trans the nonsense variant R243X (BH4 deficiency was not excluded) (PMID: 17096675). This variant is absent from the gnomAD and ESP population databases. Biochemical assays demonstrate a loss of ~50% enzyme activity (PMID: 18346471 & 21820508). Other amino acid changes at this codon have been reported. Overall, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PS3.
Met criteria codes
PM5
R297H is pathogenic in Clinvar with multiple submitters (VarID 92750)
PM2
absent from gnomAD and ESP
PS3
Reduction of enzyme activity (40 & 60%).

Not Met criteria codes
PP3
REVEL 0.578; other predictors conflicting
PM3
Detected in trans with nonsense R243X mutation; BH4 not ruled out; mild PKU?

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.
¤ Powered by BCM's Genboree.