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

CA386295865

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 37428d68-db41-4cf1-ae8f-acb16296a303

HGVS expressions

NM_001354304.2:c.707-1G>C

NC_000012.12:g.102852951C>G

CM000674.2:g.102852951C>G

NC_000012.11:g.103246729C>G

CM000674.1:g.103246729C>G

NC_000012.10:g.101770859C>G

NG_008690.1:g.69652G>C

NG_008690.2:g.110460G>C

NM_000277.1:c.707-1G>C

NM_000277.2:c.707-1G>C

NM_001354304.1:c.707-1G>C

NM_000277.3:c.707-1G>C

ENST00000307000.7:c.692-1G>C

ENST00000549247.6:n.465G>C

ENST00000553106.5:c.707-1G>C

Pathogenic

PVS1 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.707-1G>C (aka IVS6-1G>C) variant in PAH has been observed in one patient with classic PKU, in trans with pathogenic variant c.441+5G>T (PMID: 30159852). This variant is absent from controls in population databases. This variant in the -1 splice acceptor site of intron 6 results in exon skipping or use of a cryptic splice site. The variant disrupts the reading frame and is predicted to undergo nonsense mediated decay. This variant breaks the splice site in intron 6 according to computational models. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, and PP4.

PVS1

This variant in the -1 splice acceptor site of IVS6 results in exon skipping or use of a cryptic splice site. The variant disrupts the reading frame and is predicted to undergo nonsense mediated decay (NMD). This variant breaks the splice site in IVS6 according to Splice AI (0.98 - splice altering) and TraP (0.576, >97.5%ile, probably damaging).

PP4

This variant is observed in one patient with classic PKU (defined as Phe >1200 µmol/L). BH4 deficiency was not ruled out. PMID: 30159852

PubMed:30159852

PM2

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

PM3

[c.441+5G>T; c.707-1G>C]. Segregation analysis was done. PMID: 30159852

Approved on: 2020-10-15

Published on: 2020-10-15

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