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]

Link to SEPIO compliant JSON-LD document

CA1139532534

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 271e929c-43fe-41ff-9411-5c7a4c994fa3

HGVS expressions

NM_001354304.2:c.1200-3T>G

NM_000277.1:c.1200-3T>G

NM_000277.2:c.1200-3T>G

NM_001354304.1:c.1200-3T>G

NM_000277.3:c.1200-3T>G

ENST00000307000.7:c.1185-3T>G

ENST00000549247.6:n.959-3T>G

ENST00000551114.2:n.862-3T>G

ENST00000553106.5:c.1200-3T>G

ENST00000635477.1:n.304-3T>G

ENST00000635528.1:n.715-3T>G

NC_000012.12:g.102840518A>C

CM000674.2:g.102840518A>C

NC_000012.11:g.103234296A>C

CM000674.1:g.103234296A>C

NC_000012.10:g.101758426A>C

NG_008690.1:g.82085T>G

NG_008690.2:g.122893T>G

Likely Pathogenic

PP3 PP4 PM2 PM3

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

This c.1200-3T>G (aka IVS11-3T>G) intronic variant in PAH was reported in one patient with classic PKU, in trans with pathogenic variant p.Tyr204Cys. Patients with BH4 cofactor deficiency were excluded but only urinary pterin analysis was mentioned as a method of exclusion (PMID:28982351). According to in silico splicing predictions, this variant is probably damaging. The variant is absent from controls in population databases. In summary, this variant meets criteria to be classified as Likely Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP3, and PP4.

PP3

According to in silico splicing predictions, this variant is probably damaging (TraP score 0.517 > 97.5th percentile). Splice AI agrees that this variant is splice-altering (Splice AI score = 0.95).

PP4

This variant was observed in one patient with classic PKU (Phe = 2436 µmol/L). Patients with BH4 cofactor deficiency were excluded but only urinary pterin analysis was mentioned as a method of exclusion. PMID: 28982351

PubMed:28982351

PM2

This variant is absent from controls in gnomAD, ExAC, and 1000 Genomes population databases.

PM3

This variant was detected in trans with pathogenic variant p.EX6-96A<G. Segregation analysis was done. PMID: 28982351

Approved on: 2020-10-16

Published on: 2020-10-16

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