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.794G>A (p.Cys265Tyr)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229763

102836 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: cd09d332-2e68-426f-a5a2-6f716599b375

Approved on: 2022-02-25

Published on: 2022-04-16

HGVS expressions

NM_000277.2:c.794G>A

NM_000277.2(PAH):c.794G>A (p.Cys265Tyr)

NC_000012.12:g.102852863C>T

CM000674.2:g.102852863C>T

NC_000012.11:g.103246641C>T

CM000674.1:g.103246641C>T

NC_000012.10:g.101770771C>T

NG_008690.1:g.69740G>A

NG_008690.2:g.110548G>A

ENST00000553106.6:c.794G>A

ENST00000307000.7:c.779G>A

ENST00000549247.6:n.553G>A

ENST00000553106.5:c.794G>A

NM_000277.1:c.794G>A

NM_001354304.1:c.794G>A

NM_000277.3:c.794G>A

NM_001354304.2:c.794G>A

NM_000277.3(PAH):c.794G>A (p.Cys265Tyr)

Likely Pathogenic

PP4_Moderate PM2 PP3 PS3_Supporting

PM5 PM3

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.794G>A (p.Cys265Tyr) variant in PAH is reported in a Japanese patient with phenylketonuria (BH4 deficiency excluded, PMID: 9860305). This variant is absent from population databases. Multiple lines of computational evidence support a deleterious effect. PAH activity in COS cell expression system was 0% (PMID: 9860305). In summary, this variant meets the criteria to be classified as Likely pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PP4_moderate, PM2, PS3_supporting, PP3.

PP4_Moderate

Detected in a Japanese patient with PKU. Patients with BH4 deficiency were excluded based on the absence of neurologic deterioration on a low phenylalanine diet, analysis of dihydropteridine reductase activity in red blood cells, biopterin loading test, and/or pteridine analysis of urine. PMID: 9860305

PM2

Not found in ExAC/gnomAD or 1000 genomes.

PP3

computational evidence supports deleterious effect: Damaging in SIFT, MutationTaster; Probably damaging in PP2; REVEL=0.913.

PS3_Supporting

PAH activity in COS cell expression system, C265Y 0% activity PMID: 9860305. This PMID approved for PS3_Supp on PAH VCEP call 2/25/22.

PM5

C265G has no interpretation in ClinVar

PM3

2nd allele/genotype not reported

Curation History

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