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:c.353-2A>T

CA16020772

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 90537846-008a-4f47-b5d7-7c22f7800197

HGVS expressions

NM_000277.3:c.353-2A>T

NC_000012.12:g.102877552T>A

CM000674.2:g.102877552T>A

NC_000012.11:g.103271330T>A

CM000674.1:g.103271330T>A

NC_000012.10:g.101795460T>A

NG_008690.1:g.45051A>T

NG_008690.2:g.85859A>T

ENST00000553106.6:c.353-2A>T

ENST00000307000.7:c.338-2A>T

ENST00000549111.5:n.449-2A>T

ENST00000550978.6:c.337-2A>T

ENST00000551337.5:c.353-2A>T

ENST00000551988.5:n.442-2A>T

ENST00000553106.5:c.353-2A>T

NM_000277.1:c.353-2A>T

NM_000277.2:c.353-2A>T

NM_001354304.1:c.353-2A>T

NM_001354304.2:c.353-2A>T

Pathogenic

PVS1 PM3 PP4_Moderate PM2_Supporting

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.353-2A>T variant in PAH has been reported in 1 patient with classic PKU, detected in trans with p.R111*. BH4 deficiency was excluded. (PP4_Moderate, PM3; PMID: 26322415). This variant is absent from controls in ExAC/gnomAD, 1000 Genomes, or ESP (PM2_supporting). It is a null variant (canonical +/- 1 or 2 splice sites) in a gene where LOF is a known mechanism of disease, exon skipping disrupts reading frame, and is predicted to undergo NMD. Coding exon 4 is present in biologically-relevant transcript. (PVS1) In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2_supporting, PM3, PP4_Moderate.

PVS1

Null variant (canonical +/- 1 or 2 splice sites) in a gene where LOF is a known mechanism of disease. Exon skipping disrupts reading frame. Predicted to undergo NMD. Coding exon 4 is present in biologically-relevant transcript.

PM3

detected in trans with p.R111* PMID: 26322415

c.[353-2A>T ];[331C>T ], p.[(?)];[R111*]. All mutations identified in patients were confirmed by analyzing parental DNA. When mutation loci were detected in patients, the same locus of the parental sample was amplified by PCR and analyzed by Sanger automated sequencing. PubMed:26322415

PP4_Moderate

c.353-2A>T identified in 1 patient with classic PKU. BH4 deficiency was excluded. PMID: 26322415

c.353-2A>T identified in 1 patient with classic PKU. All patients fulfilled the diagnostic criteria of PKU, with a blood phenylalanine concentration >2 mg/dl. BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes. PubMed:26322415

PM2_Supporting

Absent from controls in ExAC/gnomAD, 1000 Genomes, or ESP

Approved on: 2023-12-30

Published on: 2023-12-30

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