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(PAH):c.442-1G>A

CA229550

594 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: aa4ba2e7-5604-4e53-ad0b-f24f7ed4339c

Approved on: 2019-04-09

Published on: 2019-04-09

HGVS expressions

NM_000277.1:c.442-1G>A

NM_000277.1(PAH):c.442-1G>A

NC_000012.12:g.102866664C>T

CM000674.2:g.102866664C>T

NC_000012.11:g.103260442C>T

CM000674.1:g.103260442C>T

NC_000012.10:g.101784572C>T

NG_008690.1:g.55939G>A

NG_008690.2:g.96747G>A

NM_000277.2:c.442-1G>A

NM_001354304.1:c.442-1G>A

NM_000277.3:c.442-1G>A

ENST00000307000.7:c.427-1G>A

ENST00000549111.5:n.538-1G>A

ENST00000551988.5:n.530+10798G>A

ENST00000553106.5:c.442-1G>A

Pathogenic

PVS1 PM2 PP4_Moderate

PS3 PM3

Evidence Links 3

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

PAH-specific ACMG/AMP criteria applied: PM2: Not present in ExAC or 1000 genomes (PMID:9860305); PVS1: Canonical -1 splice site where LOF is a known mechanism of disease, exon skipping disrupts reading frame, and is predicted to undergo NMD. Coding exon 5 is present in biologically-relevant transcript. PP4_Moderate: Reported in a mild PKU patient. BH4 deficiency assessed. (PMID:14681498). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PVS1, PP4_Moderate).

PVS1

Canonical -1 splice site

PM2

Not present in ExAC or 1000 genomes

7.3 % in Japanese PubMed:9860305

PP4_Moderate

Reported in a mild PKU patient. BH4 deficiency assessed.

The 12 HPA patients detected by neonatal PKU screening had normal amount of pteridine in urine or serum before BH4 loading, and also had normal dihydropteridine reductase activity according to the test using the Guthrie card. Blood phenylalanine concentrations at screening were in the range of 2.0–12.0 mg/dL. All patients were diagnosed with mild PKU. Case 9 had IVS4-1g>a. PubMed:14681498

PS3

States IVS4-1g>a have no activity, associated with HPA

States IVS4-1g>a have no activity, associated with HPA PubMed:14681498

PM3

Found in trans with A373T, IVS4nt-1 is the pathogenic variant

A373T/IVS4nt-1 PubMed:21307867

A373T/IVS4nt-1 PubMed:14681498

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