Variant: NM_000277.3(PAH):c.578_579CT[1] (p.Leu194fs)

CA229632

102741 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

UUID: 45d316d3-b5e7-4926-ac80-e3bf756f76b9

Approved on: 2020-10-30

Published on: 2020-10-30

HGVS expressions

NM_000277.3:c.578_579CT[1]
NM_000277.3(PAH):c.578_579CT[1] (p.Leu194fs)
NC_000012.12:g.102855263_102855264del
CM000674.2:g.102855263_102855264del
NC_000012.11:g.103249041_103249042del
CM000674.1:g.103249041_103249042del
NC_000012.10:g.101773171_101773172del
NG_008690.1:g.67341_67342del
NG_008690.2:g.108149_108150del
NM_000277.1:c.580_581del
NM_000277.2:c.580_581del
NM_001354304.1:c.580_581del
NM_000277.3:c.580_581del
NM_001354304.2:c.580_581del
ENST00000307000.7:c.565_566del
ENST00000549111.5:n.676_677del
ENST00000553106.5:c.580_581del

Pathogenic

• Met criteria codes: PM2 PM3_Supporting PP4 PVS1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.578_579del PAH variant has been identified in at least one patient with classic PKU (PMID: 26666653). The patient was compound heterozygous with the pathogenic variant Leu348Val (ClinVar 92727). This variant is absent from 1000G, ESP, and gnomAD databases. This variant leads to the frameshift Leu194GlufsTer5, creating a stop codon in exon 6 of 13 which is predicted to cause NMD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PP4, PM2, PM3_supporting.

Met criteria codes

• PM2: The variant is absent from population databases including gnomAD, ExAC, 1000 Genomes, and ESP.
• PM3_Supporting: At least one patient has been reported (PMID: 26666653) compound heterozygous for c.580_581del and Leu348Val (ClinVar 92727, Pathogenic by multiple submitters). Confirmation of trans phase was not reported.
• PP4: At least one proband with this variant has been described (PMID: 26666653) with the classic PKU phenotype and PHE >1200umol/L. Exclusion of defects in BH4 cofactor metabolism was not reported.
• PVS1: The c.578_579del variant leads to the frameshift Leu194GlufsTer5, creating a stop codon in exon 6 of 13 which is predicted to cause NMD.