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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CA16020733

805828 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 05f21f32-b0f9-4eca-84f5-fd9d2bfd7711

Approved on: 2019-04-09

Published on: 2019-04-09

HGVS expressions

NM_001354304.1:c.168+2T>C

NM_000277.1:c.168+2T>C

NM_000277.2:c.168+2T>C

NM_000277.3:c.168+2T>C

NM_001354304.2:c.168+2T>C

ENST00000307000.7:c.153+2T>C

ENST00000546844.1:c.168+2T>C

ENST00000548677.2:n.255+2T>C

ENST00000548928.1:n.90+2T>C

ENST00000549111.5:n.264+2T>C

ENST00000550978.6:n.152+2T>C

ENST00000551337.5:c.168+2T>C

ENST00000551988.5:n.257+2T>C

ENST00000553106.5:c.168+2T>C

ENST00000635500.1:n.136+2T>C

NC_000012.12:g.102912789A>G

CM000674.2:g.102912789A>G

NC_000012.11:g.103306567A>G

CM000674.1:g.103306567A>G

NC_000012.10:g.101830697A>G

NG_008690.1:g.9814T>C

NG_008690.2:g.50622T>C

Pathogenic

PP4_Moderate PM2 PM3 PVS1_Strong

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.168+2T>C variant in PAH was reported in one patient with PKU (BH4 deficiency excluded) in trans with p.R243Q (PP4_Moderate, PM3; PMID: 28982351). This variant is absent from population databases, including gnomAD (PM2). This variant occurs at a canonical splice site, which will result in abnormal splicing at the donor site of intron 2 where LOF is a known mechanism of disease, exon skipping preserves reading frame, but the altered region is critical to protein function (14 non-truncating pathogenic variants in the region). (PVS1_strong). In summary, this variant meets the criteria to be classified pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PVS1_strong, PM2, PM3.

PP4_Moderate

detected in one patient with PKU. BH4 cofactor deficiency was ruled out. Phenylalanine pre treatment was > 120 uM. PMID: 28982351

Variant detected in a cohort of phenylketonuria in one patient with a pathogenic missense (p.R243Q) in trans. BH4 cofactor deficiency was ruled out. Phenylalanine pre treatment was > 120 uM. PubMed:28982351

PM2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM3

detected in trans with p.R243Q (P, 7 submitters)

Variant detected in one patient with a pathogenic missense (p.R243Q) in trans. PubMed:28982351

PVS1_Strong

Null variant (canonical +/- 1 or 2 splice sites) where LOF is a known mechanism of disease, exon skipping preserves reading frame, but the altered region is critical to protein function (14 non-truncating pathogenic variants in the region).

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