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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CA16020732

805827 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: df45121c-fb1b-4d56-85d2-ff3ee7256e36

Approved on: 2019-04-09

Published on: 2019-04-09

HGVS expressions

NM_001354304.1:c.168+1G>T

NM_000277.1:c.168+1G>T

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

NM_000277.3:c.168+1G>T

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

ENST00000307000.7:c.153+1G>T

ENST00000546844.1:c.168+1G>T

ENST00000548677.2:n.255+1G>T

ENST00000548928.1:n.90+1G>T

ENST00000549111.5:n.264+1G>T

ENST00000550978.6:n.152+1G>T

ENST00000551337.5:c.168+1G>T

ENST00000551988.5:n.257+1G>T

ENST00000553106.5:c.168+1G>T

ENST00000635500.1:n.136+1G>T

NC_000012.12:g.102912790C>A

CM000674.2:g.102912790C>A

NC_000012.11:g.103306568C>A

CM000674.1:g.103306568C>A

NC_000012.10:g.101830698C>A

NG_008690.1:g.9813G>T

NG_008690.2:g.50621G>T

Likely Pathogenic

PP4 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+1G>T has been reported in compound heterozygote state in 2 patients with PKU (BH4 deficiency not excluded) (PMID: 24368688). The variants in trans include: R111*, and L249F are both confirmed pathogenic (PM3). This variant is absent from population databases (PM2). 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). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria: PM2, PM3, PP4, PVS1_strong.

PP4

This variant was reported in compound heterozygote state in two patients with PKU. Normal BH4 metabolism was not confirmed. PMID: 24368688

This variant was reported in compound heterozygote state in two patients with PKU. The second variants included: R111* and the pathogenic L249F. Normal BH4 metabolism was not confirmed. PubMed:24368688

PM2

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

PM3

detected with p.R111* (P, 6 submitters) and p.L249F (P, 6 submitters). PMID: 24368688

The second variants included: R111* and the pathogenic L249F. PubMed:24368688

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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