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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CA16020846

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 00ac6a3d-eae6-4988-8c79-3396eb3bb017

HGVS expressions

NM_000277.3:c.707-2del

NC_000012.12:g.102852952del

CM000674.2:g.102852952del

NC_000012.11:g.103246730del

CM000674.1:g.103246730del

NC_000012.10:g.101770860del

NG_008690.1:g.69651del

NG_008690.2:g.110459del

NM_000277.1:c.707-2del

NM_000277.2:c.707-2del

NM_001354304.1:c.707-2del

ENST00000307000.7:c.692-2del

ENST00000549247.6:n.464del

ENST00000553106.5:c.707-2del

Pathogenic

PM3 PM2 PVS1 PP4

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.707-2delA variant in PAH has been reported in one patient, who carried a second pathogenic missense variant (p.Pro281Leu; BH4 deficiency not ruled out) (PMID: 19292873). The pre-treatment serum phenylalanine was reported at > 1500 micromolar. This variant is absent from gnomAD and ESP population databases, and disrupts the canonical splice acceptor site of intron 6, resulting in a frameshift and truncated protein (PMID: 19292873). Overall, the c.707-2delA variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PVS1, PP4.

PM3

Seen in trans with pathogenic p.P281L.

Seen in trans with pathogenic p.P281L. PubMed:19292873

PM2

absent from gnomAD and ESP.

PVS1

Deletion of a canonical splice site (-2). Direct sequencing of cDNA confirmed the skipping of the whole 136 bp exon7 and showed an altered junction between exons 6 and 8. This process causes a new ORF containing a frameshift, which results in the truncated p.T236MfsX60 protein due to a premature termination after 60 codons.

PP4

detected in a patient with HPA, BH4 deficiency assessment not reported. PMID: 19292873

Approved on: 2019-07-15

Published on: 2019-07-15

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