NM_000277.3:c.344_347del

102652 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

UUID: 558984a6-51b6-4793-b0f2-86e7c5b8d83c

Approved on: 2022-10-14

Published on: 2022-10-14

HGVS expressions

NM_000277.3:c.344_347del
NM_000277.3(PAH):c.344_347del (p.Lys115fs)

Pathogenic

• Met criteria codes: PVS1 PM3_Supporting PM2 PP4

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Evidence submitted by expert panel

Phenylketonuria VCEP

This c.344_347del (p.Lys115fs) variant in PAH was detected with the c.1315+1G>A pathogenic variant and the c.1066-14C>G likely pathogenic variant in multiple patients with PKU, phasing was not available (PMID: 11207989, 28676969, 25551302). This variant was absent in population databases. This is a frameshift variant in exon 3 of 13 coding exons with termination at position 194 predicted to undergo nonsense mediated decay. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3_Supporting, PP4.

Met criteria codes

• PVS1: Frameshift variant predicted to undergo NMD. Termination occurs at position 194 (115+79). Located in exon 3 out of 13 coding exons, not in the last 50bp of exon 12.
• PM3_Supporting: This variant was detected with the c.1315+1G>A pathogenic variant (no phasing available) PMID: 25551302. It was detected with the likely pathogenic variant c.1066-14C>G. PMID: 11207989. points=0.75.
• PM2: This variant is absent from population databases gnomAD and ExAC
• PP4: Variant was detected in multiple patients with PKU. PMID: 11207989, 28676969, 25551302.