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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CA16020971

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: c8331140-e6c4-4def-805a-576dce56dc2f

HGVS expressions

NM_001354304.2:c.1215_1219del

NC_000012.12:g.102840498_102840502del

CM000674.2:g.102840498_102840502del

NC_000012.11:g.103234276_103234280del

CM000674.1:g.103234276_103234280del

NC_000012.10:g.101758406_101758410del

NG_008690.1:g.82103_82107del

NG_008690.2:g.122911_122915del

NM_000277.1:c.1215_1219del

NM_000277.2:c.1215_1219del

NM_001354304.1:c.1215_1219del

NM_000277.3:c.1215_1219del

ENST00000307000.7:c.1200_1204del

ENST00000551114.2:n.877_881del

ENST00000553106.5:c.1215_1219del

ENST00000635477.1:n.319_323del

ENST00000635528.1:n.730_734del

Pathogenic

PP4_Moderate 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.1215_1219del (p.Ile406SerfsTer15) in PAH was found in 1 Chinese patient with Phe levels >120 umol/L (PMID: 26322415). BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PP4-Moderate). This is a frameshift variant in exon 12 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 (PVS1). Variant was found in trans with pathogenic variant p.P147L (PMID: 26322415) (PM3). Parental DNA was sequenced via NGS. The variant is 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-Moderate, PM2.

PP4_Moderate

Variant was found in 1 Chinese patient with Phe levels >120 umol/L (PMID: 26322415). BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes.

PubMed:26322415

PM3

Variant was found in trans with p.P147L (Likely Pathogenic 3 reports) in a patient with mPKU. (PMID: 26322415). Parental DNA was sequenced via NGS.

PM2

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

PVS1

This is a frameshift variant in exon 12 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.

Approved on: 2020-05-14

Published on: 2020-05-14

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