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(PAH):c.926C>T (p.Ala309Val)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA220592

92753 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: db2881e3-3790-4e61-95e9-4ee16b4291d4

Approved on: 2018-08-10

Published on: 2019-04-05

HGVS expressions

NM_000277.1:c.926C>T

NM_000277.1(PAH):c.926C>T (p.Ala309Val)

NC_000012.12:g.102846938G>A

CM000674.2:g.102846938G>A

NC_000012.11:g.103240716G>A

CM000674.1:g.103240716G>A

NC_000012.10:g.101764846G>A

NG_008690.1:g.75665C>T

NG_008690.2:g.116473C>T

NM_000277.2:c.926C>T

NM_001354304.1:c.926C>T

NM_000277.3:c.926C>T

ENST00000307000.7:c.911C>T

ENST00000549247.6:n.685C>T

ENST00000551114.2:n.588C>T

ENST00000553106.5:c.926C>T

ENST00000635477.1:n.74-2507C>T

ENST00000635528.1:n.441C>T

Pathogenic

PS3 PP3 PP4 PM2 PM3

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

PAH-specific ACMG/AMP criteria applied: PM2: Low frequency. 1.0e-5; PP3: All databases agree on damaging effect. REVEL=0.921; PS3: Enzyme activity = 30% (Ho, 2008) (PMID:18590700); PM3: Single patient with classic PKU, c.842C>T (pathogenic in ClinVar) / c.926C>T (PMID:26666653); PP4: Single patient with classic PKU (>1200umol/L), BH4 defect not excluded (PMID:26666653). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PS3, PM3, PP4).

PS3

Enzyme activity = 30% (Ho, 2008)

PAH activity analysis. Site directed mutagenesis, transfected COS-1 cells. Enzyme activity measured as conversion of L-[14C]phe to L-[14C]tyr. Use both standard cDNA expression system and a new Intinic plasmid system which incorporates intronic sequences. Standard cDNA method demonstrates 30% and intinic system demonstrates 14% residual enzyme activity. PubMed:18590700

PP3

All databases agree on damaging effect. REVEL=0.921

PP4

Single patient with classic PKU (>1200umol/L), BH4 defect not excluded

Genotype-phenotype association in French patients with PKU. 364 patients, 24hr BH4 loading test. PubMed:26666653

PM2

Low frequency. 1.0e-5

PM3

Single patient with classic PKU, c.842C>T (pathogenic in ClinVar) / c.926C>T

Genotype-phenotype association in French patients with PKU. 364 patients, 24hr BH4 loading test. PubMed:26666653

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.