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_000277.2(PAH):c.168+1G>A

CA229452

102604 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: fd35f7ad-8305-4adf-bce7-3cebca7e1c29

Approved on: 2018-12-09

Published on: 2019-08-17

HGVS expressions

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

NM_000277.2(PAH):c.168+1G>A

NC_000012.12:g.102912790C>T

CM000674.2:g.102912790C>T

NC_000012.11:g.103306568C>T

CM000674.1:g.103306568C>T

NC_000012.10:g.101830698C>T

NG_008690.1:g.9813G>A

NG_008690.2:g.50621G>A

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

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

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

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

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

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

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

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

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

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

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

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

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

Pathogenic

PVS1 PP4_Moderate PM3 PM2

Evidence Links 3

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.168+1G>A variant in PAH is at a canonical splice site at intron 3, and is absent in all population databases. It has been identified in trans with a pathogenic variant (Ho, 2014), and as a homozygous variant (PMID: 18294361) in patients with phenylketonuria. Defects in BH4 metabolism were excluded as a cause of elevated phenylalanine in two patients (PMID: 24368688, 8807331). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4_Moderate.

PVS1

canonical splice site at intron 3

PP4_Moderate

BH4 defect excluded in all patients. Single patient with classic PKU (PMID: 24368688). Phe in an independent patient 1990umol/L (PMID: 8807331)

Single patient with phe 1990umol/L PubMed:8807331

BH4 defect excluded in all patients PubMed:24368688

PM3

in trans with c.745C>T (Ho, 2014), and homozgyous (PMID: 18294361)

in trans with c.745C>T PubMed:24368688

homozygous in a single patient PubMed:18294361

PM2

Absent from ExAC and gnomAD

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