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_000277.1:c.47_48dup

CA16020717

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 7db8ceb1-259a-4876-bd1f-5dcff1666777

HGVS expressions

NM_000277.1:c.47_48dup

NC_000012.12:g.102917087_102917088dup

CM000674.2:g.102917087_102917088dup

NC_000012.11:g.103310865_103310866dup

CM000674.1:g.103310865_103310866dup

NC_000012.10:g.101834995_101834996dup

NG_008690.1:g.5519_5520dup

NG_008690.2:g.46327_46328dup

ENST00000553106.6:c.47_48dup

ENST00000307000.7:c.-101_-100dup

ENST00000546844.1:c.47_48dup

ENST00000547319.1:n.358_359dup

ENST00000549111.5:n.143_144dup

ENST00000550978.6:c.31_32dup

ENST00000551337.5:c.47_48dup

ENST00000551988.5:n.136_137dup

ENST00000553106.5:c.47_48dup

ENST00000635500.1:n.29-4186_29-4185dup

NM_000277.2:c.47_48dup

NM_001354304.1:c.47_48dup

NM_000277.3:c.47_48dup

NM_001354304.2:c.47_48dup

Pathogenic

PVS1 PM2_Supporting PP4_Moderate

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specification: ClinGen PAH Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.47_48dup (p.Asp17LeufsTer22) variant in PAH is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 1/13 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is reported on 3 alleles of patients with phenylketonuria, with BH4 deficiency excluded (PP4_moderate, PMID: 21147011). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PVS1, PP4_moderate, PM2_supporting. (Phenylketonuria VCEP specifications version 1).

PVS1

Frameshift variant in exon 1 predicted to undergo NMD

PM2_Supporting

absent from ExAC, gnomAD v2.1.1, 1000G, ESP

PP4_Moderate

c.48_49insCT seen in 3 PKU alleles. BH4 deficiency excluded (PTS and QDPR analyzed). Upgraded per ClinGen PAH EP. PMID: 21147011

588 hyperphenylalaninemic patients were investigated. Assessment included PAH gene and genes of the BH4 synthesis/recycling pathways (PTS and QDPR). c.48_49insCT seen in 3 alleles. PubMed:21147011

Approved on: 2023-10-15

Published on: 2023-10-15

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