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_000277.3(PAH):c.578_579CT[1] (p.Leu194fs)

CA229632

102741 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

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

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

PVS1 PM3_Supporting PP4 PM2

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

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.

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.

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.

PubMed:26666653

PM2

The variant is absent from population databases including gnomAD, ExAC, 1000 Genomes, and ESP.

Approved on: 2020-10-30

Published on: 2020-10-30

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