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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CA16020766

Gene: PAH
Condition: phenylketonuria
Inheritance Mode: Autosomal recessive inheritance
UUID: 893a2c5e-12c2-4906-b639-8dcd2aadf73d

HGVS expressions

NM_001354304.2:c.324_328del
NM_000277.1:c.324_328del
NM_000277.2:c.324_328del
NM_001354304.1:c.324_328del
NM_000277.3:c.324_328del
ENST00000307000.7:c.309_313del
ENST00000546844.1:c.324_328del
ENST00000548928.1:n.246_250del
ENST00000549111.5:n.420_424del
ENST00000550978.6:n.308_312del
ENST00000551337.5:c.324_328del
ENST00000551988.5:n.413_417del
ENST00000553106.5:c.324_328del
NC_000012.12:g.102894759_102894763del
CM000674.2:g.102894759_102894763del
NC_000012.11:g.103288537_103288541del
CM000674.1:g.103288537_103288541del
NC_000012.10:g.101812667_101812671del
NG_008690.1:g.27840_27844del
NG_008690.2:g.68648_68652del

Pathogenic

Met criteria codes 3
PP4 PM2 PVS1

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Phenylketonuria VCEP
This variant c.324_328del (p.Glu108AspfsTer4) in PAH was reported in at least 1 Czech patient with PAH deficiency (paper did not specify how many patients had this variant) (PMID: 23357515), although a defect in BH4 metabolism was not excluded. This is a frameshift 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. This variant is absent from population databases. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4.
Met criteria codes
PP4
PP4_met: This variant was documented in at least 1 patient with HPA (PMID: 23357515). 23357515, Réblová - This variant was documented in at least 1 Czech patient (paper did not mention how many patients had this variant) with HPA. The paper defined HPA in their intro: "HPA patients can be classified based on their off-diet diagnostic plasma Phe levels as classical PKU (Phe above 1200 μmol/L), mild PKU (Phe between 600 and 1200 μmol/L) or non-PKU HPA (Phe between 120 and 600 μmol/L)."

PM2
PM2_met: This variant is absent from population databases gnomAD and ExAC.
PVS1
PVS1_met: This is a frameshift 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. Loss of function is a known mechanism of disease: 175 pathogenic null variants reported in ClinVar across 13 different exons, 20 of which are in exon 3.
Approved on: 2020-10-15
Published on: 2020-10-15
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