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]

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CA16020946

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 39507c47-d45b-462f-9aaf-5205e361c94e

HGVS expressions

NM_000277.3:c.1129T>G

NM_000277.1:c.1129T>G

NM_000277.2:c.1129T>G

NM_001354304.1:c.1129T>G

NM_001354304.2:c.1129T>G

ENST00000307000.7:c.1114T>G

ENST00000549247.6:n.888T>G

ENST00000551114.2:n.791T>G

ENST00000553106.5:c.1129T>G

ENST00000635477.1:n.233T>G

ENST00000635528.1:n.644T>G

NC_000012.12:g.102843716A>C

CM000674.2:g.102843716A>C

NC_000012.11:g.103237494A>C

CM000674.1:g.103237494A>C

NC_000012.10:g.101761624A>C

NG_008690.1:g.78887T>G

NG_008690.2:g.119695T>G

Likely Pathogenic

PM3 PM2 PP3 PP4_Moderate

PM5

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1129T>G (p.Tyr377Asp) variant in PAH has been reported in 1 Armenian individual with classic PKU (BH4 deficiency ruled out) (PP4_Moderate; PMID: 21890392). This variant is absent in population databases (PM2). This variant was detected in trans with c.1066-11G>A (Pathogenic in ClinVar) (PM3, PMID: 21890392). This variant is prediction to be deleterious by SIFT, PolyPhen, and MutationTaster, and REVEL = 0.932 (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP3, PP4_Moderate.

PM3

PMID: 21890392 - This patient (case #8) carried the previously described variant c.1066-11G>A (VarID 607, P, 10 submitters) which was inherited on the paternal allele. Y377D inherited on the maternal allele. = 1.0 point

PM2

Variant absent from population databases

PP3

Deleterious effect predicted by SIFT, PolyPhen, and MutationTaster. REVEL = 0.932.

PP4_Moderate

PMID: 21890392 - T377D detected in Armenian patient (case #9) through sequence analysis of PAH exons (classic PKU, serum Phe = 20-30mg/dl, BH4 deficiency ruled out via HPLC to measure pterin concentration)

PubMed:21890392

PM5

c.1130A>G (p.Y377C), not assertion in ClinVar (ClinVar ID: 102534). Curation in progress by PAH VCEP, currently classified as Likely Pathogenic.

Approved on: 2020-05-09

Published on: 2020-05-09

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