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

Variant: NM_001354304.2:c.280_283del

CA2497030226

Gene: N/A

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: c490ee6e-f09c-499e-beb7-69fa038501b7

HGVS expressions

NM_001354304.2:c.280_283del

Pathogenic

PVS1 PP4 PM2

PM3

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specification: ClinGen PAH Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.280_283del (p.Ile94SerfsTer4) variant in PAH is a frameshift variant predicted to cause termination at amino acid 98 resulting in nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. It has been detected in a patient with classic PKU with likely pathogenic variant p.P281L, phase unconfirmed (PMID: 26210745). This variant is absent in population databases. In summary, this variant meets criteria to be classified as Pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PM2, PP4, PVS1.

PVS1

This is a frameshift variant which termination predicted at amino acid 98 resulting in NMD, not located in last exon or last 50bp of preliminary exon. Coding exon number 3 out of 13 coding exons (3 out of total exons).

PP4

Detected in one patient with classic PKU. Peripheral whole blood was collected on patients with classical Phenylketonuria (the lowest blood phenylalanine 1080 μmol/l (18 mg/dl)) (PMID: 26210745)

PM2

Absent from controls in gnomAD, ExAC, 1000 Genomes, or ESP

PM3

Detected with c.842C>T (p.P281L) which is classified as likely pathogenic in ClinVar (0.25 points). Phase is unconfirmed. (PMID: 26210745)

Approved on: 2023-03-16

Published on: 2023-03-16

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