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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CA913184971

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: e27510df-6543-47c4-b143-480135f094f6

Approved on: 2019-04-03

Published on: 2019-08-16

HGVS expressions

NM_000277.3:c.184_185insCTGA

NC_000012.12:g.102894902_102894903insTCAG

CM000674.2:g.102894902_102894903insTCAG

NC_000012.11:g.103288680_103288681insTCAG

CM000674.1:g.103288680_103288681insTCAG

NC_000012.10:g.101812810_101812811insTCAG

NG_008690.1:g.27700_27701insCTGA

NG_008690.2:g.68508_68509insCTGA

NM_000277.1:c.184_185insCTGA

NM_000277.2:c.184_185insCTGA

NM_001354304.1:c.184_185insCTGA

ENST00000307000.7:c.169_170insCTGA

ENST00000546844.1:c.184_185insCTGA

ENST00000548677.2:n.271_272insCTGA

ENST00000548928.1:n.106_107insCTGA

ENST00000549111.5:n.280_281insCTGA

ENST00000550978.6:n.168_169insCTGA

ENST00000551337.5:c.184_185insCTGA

ENST00000551988.5:n.273_274insCTGA

ENST00000553106.5:c.184_185insCTGA

ENST00000635500.1:n.152_153insCTGA

Pathogenic

PP4 PM2 PVS1

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.184_187insCTGA variant in PAH has been previously reported as a single (heterozygous) mutation in 1 Chinese PKU case (PMID: 26503515; PP4). The variant is a frameshift variant occurring in exon 3 of 13 in the in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (see PMID: 30192042) (PVS1). It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4.

PP4

The c.184_187insCTGA variant in PAH has been previously reported as a single (heterozygous) mutation in 1 Chinese PKU case (PMID: 26503515); no patient-specific information was provided regarding the type of PKU, but included patients had plasma phe > 120 umol/L.

The c.184_187insCTGA variant in PAH has been previously reported as a single (heterozygous) mutation in 1 Chinese PKU case (PMID: 26503515); no further patient-specific information was provided regarding the type of PKU and/or the proband’s genotype. Methods report patients were diagnosed at birth either through a neonatal screening program or based on clinical presentation. biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected. These patients were classified into one of three separate phenotype categories according to their pretreatment plasma Phe levels, including mild hyperphenylalaninaemia (Phe 120–600umol/L), mild PKU(Phe 600-1200μmol/L), and classic PKU (Phe>1200μmol/L)47. PubMed:26503515

PM2

It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2).

PVS1

The variant is a frameshift variant occurring in exon 3 of 13 in the in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (see PMID: 30192042) (PVS1).

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