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]

Variant: NM_000277.3(PAH):c.970-1G>A

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA267690

120298 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 98f65ae4-c892-4f08-8f00-efd4319410ba

Approved on: 2020-04-30

Published on: 2020-04-30

HGVS expressions

NM_000277.3:c.970-1G>A

NM_000277.3(PAH):c.970-1G>A

NM_000277.1:c.970-1G>A

NM_000277.2:c.970-1G>A

NM_001354304.1:c.970-1G>A

NM_001354304.2:c.970-1G>A

ENST00000307000.7:c.955-1G>A

ENST00000549247.6:n.729-1G>A

ENST00000551114.2:n.632-1G>A

ENST00000553106.5:c.970-1G>A

ENST00000635477.1:n.74-1G>A

ENST00000635528.1:n.485-1G>A

NC_000012.12:g.102844432C>T

CM000674.2:g.102844432C>T

NC_000012.11:g.103238210C>T

CM000674.1:g.103238210C>T

NC_000012.10:g.101762340C>T

NG_008690.1:g.78171G>A

NG_008690.2:g.118979G>A

Likely Pathogenic

PVS1_Strong PM2

PP4

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.970-1G>A variant in PAH is a splice-site variant predicted to result in skipping of exon 10, which is a key region of the encoded enzyme (PVS1_Strong). It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It is reported Likely Pathogenic for PKU in Clinvar by a single lab (ID 120298), without further information. It has also been reported in the BioPKU database as an online submission in 2013, without further information. Classification: Likely Pathogenic Supporting ACMG criteria: PVS1_Strong, PM2

PVS1_Strong

The c.970-1G>A variant in PAH is a splice-site variant predicted to result in skipping of exon 10, which is a key region of the encoded enzyme (PVS1_Strong). *Exon 10 forms part of the PAH catalytic domain (which spans residues 143-410) and contains the Glu330 residue involved in iron binding to the active site, needed for catalysis (see PMID: 23457044; PMID: 22005392). It contains non-truncating pathogenic/likely pathogenic variants such as c.997C>T (p.Leu333Phe) (Pathogenic by ClinGen PAH VCEP; Pathogenic in Clinvar (ID 624; 2 submitters, zero stars); c.1033G>A (p.Ala345Thr) (ID 102483, 3 submitters, 3 stars; Likely Pathogenic by ClinGen PAH VCEP); and c.1042C>G (p.Leu348Val) (Pathogenic by ClinGen PAH VCEP; Pathogenic in Clinvar (ID 92727, 8 submitters, 2 stars) and associated with reduced enzyme activity (~20-40% versus wild-type). Thus, loss of exon 10 is expected to substantially diminish PAH activity. Therefore, PVS1_Strong will be applied if exon 10 is lost.

PM2

Not found in any population database

PP4

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

Curation History

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