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]

Link to SEPIO compliant JSON-LD document

CA16020787

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: bd206e71-e371-4040-8bb1-a13214fc91d3

HGVS expressions

NM_001354304.2:c.441+2T>G

NC_000012.12:g.102877460A>C

CM000674.2:g.102877460A>C

NC_000012.11:g.103271238A>C

CM000674.1:g.103271238A>C

NC_000012.10:g.101795368A>C

NG_008690.1:g.45143T>G

NG_008690.2:g.85951T>G

NM_000277.1:c.441+2T>G

NM_000277.2:c.441+2T>G

NM_001354304.1:c.441+2T>G

NM_000277.3:c.441+2T>G

ENST00000307000.7:c.426+2T>G

ENST00000549111.5:n.537+2T>G

ENST00000550978.6:n.427T>G

ENST00000551988.5:n.530+2T>G

ENST00000553106.5:c.441+2T>G

Pathogenic

PM3_Supporting 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

This c.441+2T>G variant in PAH was reported in 1 Caucasian patient with PAH deficiency (PMID: 23430918) detected with the pathogenic variant p.Arg408Trp. A defect in BH4 metabolism was not excluded. This variant is absent from population databases. This variant in the +2 splice donor site results in exon skipping, which disrupts the reading frame and is predicted to undergo nonsense mediated decay. The exon is present in biologically-relevant transcripts. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3_supporting, PP4.

PM3_Supporting

PM3_supporting: This variant was detected in trans with a pathogenic variant in 1 patient with PAH deficiency (PMID: 23430918). 23430918 - This variant was detected in trans with the pathogenic PAH variant p.Arg408Trp in 1 patient with PAH deficiency. Parental analysis was not performed to confirm compound heterozygosity.

PP4

PP4_met: This variant was documented in 1 patient with PAH deficiency (PMID: 23430918). 23430918, Sarkissian - This variant was documented in 1 Caucasian patient with PAH deficiency. All PKU patients included in this study had phenylalanine plasma concentrations >120 μM as described in the clinical trial protocols. A defect in BH4 metabolism was not excluded through a BH4 loading test, urinary pterin analysis and DHPR activity assay.

PubMed:23430918

PM2

PM2_met: This variant is absent from population databases gnomAD and ExAC.

PVS1

PVS1_met: This variant in the +2 splice donor site of IVS4 results in exon skipping or use of a cryptic splice site. The variant disrupts the reading frame and is predicted to undergo nonsense mediated decay (NMD). The exon is present in biologically-relevant transcripts. This variant breaks the splice site in IVS4 according to Splice AI (0.91 - splice-altering) and TraP (0.877, >99%ile, probably damaging).

Approved on: 2020-10-15

Published on: 2020-10-15

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