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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Variant: NM_000277.3(PAH):c.359G>A (p.Trp120Ter)

CA229522

102656 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: d5a189ba-2c37-468d-a0af-648a4a259394

HGVS expressions

NM_000277.3:c.359G>A

NM_000277.3(PAH):c.359G>A (p.Trp120Ter)

NC_000012.12:g.102877544C>T

CM000674.2:g.102877544C>T

NC_000012.11:g.103271322C>T

CM000674.1:g.103271322C>T

NC_000012.10:g.101795452C>T

NG_008690.1:g.45059G>A

NG_008690.2:g.85867G>A

NM_000277.1:c.359G>A

NM_000277.2:c.359G>A

NM_001354304.1:c.359G>A

NM_001354304.2:c.359G>A

ENST00000307000.7:c.344G>A

ENST00000549111.5:n.455G>A

ENST00000550978.6:n.343G>A

ENST00000551337.5:c.359G>A

ENST00000551988.5:n.448G>A

ENST00000553106.5:c.359G>A

Pathogenic

PVS1 PP4 PM2 PM3_Supporting

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

Variant c.359G>A (p.Trp120Ter) in PAH was found in 1 Moroccan patient with Phe levels >600 umol/L (PMID: 19786003) (PP4). This is a nonsense variant in exon 4 out of 13 coding exons, predicted to undergo nonsense mediated mRNA decay, as it is not located in the 3’-most exon or the 3’-most 50 bp of the penultimate exon. The exon is present in biologically-relevant transcripts (PVS1). Patient was found to be homozygous for p.W125X (PMID:19786003) (PM3). Parental and familial DNA was sequenced. Variant was absent from controls in gnomAD, PAGE, 100 Genomes or ESP (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied:PVS1, PM3_supporting, PP4, PM2.

PVS1

This is a nonsense variant in exon 4 out of 13 coding exons. The variant is predicted to undergo nonsense mediated mRNA decay (NMD), as it is not located in the 3’-most exon or the 3’-most 50 bp of the penultimate exon. The exon is present in biologically-relevant transcripts.

PP4

Variant p.W120X was found in 1 Moroccan patients with Phe levels >600 umol/L (PMID: 19786003).

PubMed:19786003

PM2

Absent from controls in gnomAD, PAGE, 1000 Genomes or ESP.

PM3_Supporting

1 patient was found to be homozygous for p.W125X (PMID:19786003). Parental and familial DNA was sequenced.

Approved on: 2020-05-08

Published on: 2020-05-08

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