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.829T>G (p.Tyr277Asp)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA251534

603 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: ac3ebdc5-43ab-403b-8ef9-27fff7d691ba

Approved on: 2018-08-05

Published on: 2019-04-05

HGVS expressions

NM_000277.2:c.829T>G

NM_000277.2(PAH):c.829T>G (p.Tyr277Asp)

NC_000012.12:g.102852828A>C

CM000674.2:g.102852828A>C

NC_000012.11:g.103246606A>C

CM000674.1:g.103246606A>C

NC_000012.10:g.101770736A>C

NG_008690.1:g.69775T>G

NG_008690.2:g.110583T>G

NM_000277.1:c.829T>G

NM_001354304.1:c.829T>G

NM_000277.3:c.829T>G

ENST00000307000.7:c.814T>G

ENST00000549247.6:n.588T>G

ENST00000553106.5:c.829T>G

Pathogenic

PS3 PP3 PM2 PP4_Moderate 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.829T>G (p.Tyr277Asp) variant in PAH has been reported in 2 individuals with Classic PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 8268925; PMID: 23500595). This variant has an extremely low allele frequency (1/121400) in ExAC (PM2; http://exac.broadinstitute.org). This variant has 0% enzyme activity (PS3; http://www.biopku.org/centralStore/biopku/PAH%20activity.pdf). This variant was detected in trans with L48S (Pathogenic in ClinVar) (PM3; PMID: 23500595). Computational prediction tools and conservation analysis suggest that the c.829T>G variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3

PS3

PAH activity is 0% from BioPKU

PP3

Deleterious affected predicted by SIFT and PolyPhen. Predicted A,A (damaging) by MutationTaster.

PM2

1/121400 reported in ExAC. Absent in 1000 genomes, gnomAD, and ESP.

PP4_Moderate

Found in 2 individuals with Classic PKU with BH4 deficiency excluded. PMID: 8268925; PMID: 23500595.

Found in 2 individuals with Classic PKU with BH4 deficiency excluded. PubMed:23500595

One individual reported with PKU. PubMed:8268925

PM3

Found in trans with L48S, pathogenic in ClinVar PMID: 23500595

Found in trans with L48S in two individual with Classic PKU. PubMed:23500595

PM5

Y277C (likely pathogenic in ClinVar)

Curation History

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