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]

Variant: NM_001354304.2:c.253A>T

CA16020757

Gene: PAH (HGNC:5053)

Condition: phenylketonuria (MONDO:0009861)

Inheritance Mode: Autosomal recessive inheritance

UUID: eef3b853-ba5c-4908-86b9-3bd943cd2361

Approved on: 2020-05-08

Published on: 2020-05-08

HGVS expressions

NM_001354304.2:c.253A>T

NC_000012.12:g.102894834T>A

CM000674.2:g.102894834T>A

NC_000012.11:g.103288612T>A

CM000674.1:g.103288612T>A

NC_000012.10:g.101812742T>A

NG_008690.1:g.27769A>T

NG_008690.2:g.68577A>T

NM_000277.1:c.253A>T

NM_000277.2:c.253A>T

NM_001354304.1:c.253A>T

NM_000277.3:c.253A>T

ENST00000307000.7:c.238A>T

ENST00000546844.1:c.253A>T

ENST00000548677.2:n.340A>T

ENST00000548928.1:n.175A>T

ENST00000549111.5:n.349A>T

ENST00000550978.6:n.237A>T

ENST00000551337.5:c.253A>T

ENST00000551988.5:n.342A>T

ENST00000553106.5:c.253A>T

Pathogenic

PP4 PM3 PM2 PVS1

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

Variant c.253A>T (p.Lys85Ter) in PAH was found in 3 Moroccan patients with Phe levels >600 umol/L (PMID: 19786003) (PP4). This is a nonsense variant in exon 3 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). Three patients were homozygous for p.K85X (PMID: 19786003) (PM3). Parental and familial DNA were sequenced. The 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, PP4, PM2.

PP4

Variant p.K85X was found in 3 Moroccan patients with Phe levels >600 umol/L (PMID: 19786003).

PubMed:19786003

PM3

3 patients were found to be homozygous for p.K85X (PMID: 19786003). Parental and familial DNA were sequenced.

PM2

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

PVS1

This is a nonsense variant in exon 3 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.

Curation History

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