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.707-2A>G

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229704

102794 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 854f6ce8-5399-491b-9988-4dcb77d81850

Approved on: 2020-12-07

Published on: 2021-03-03

HGVS expressions

NM_000277.3:c.707-2A>G

NM_000277.3(PAH):c.707-2A>G

NC_000012.12:g.102852952T>C

CM000674.2:g.102852952T>C

NC_000012.11:g.103246730T>C

CM000674.1:g.103246730T>C

NC_000012.10:g.101770860T>C

NG_008690.1:g.69651A>G

NG_008690.2:g.110459A>G

ENST00000307000.7:c.692-2A>G

ENST00000553106.5:c.707-2A>G

NM_000277.1:c.707-2A>G

NM_000277.2:c.707-2A>G

NM_001354304.1:c.707-2A>G

NM_001354304.2:c.707-2A>G

Pathogenic

PVS1 PP4 PM3 PM2

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

This c.707-2A>G variant in PAH was reported in trans with pathogenic variant p.Arg408Trp in 1 Bulgarian patient with PAH deficiency (PMID: 1563085). This variant is absent from population databases gnomAD, 1000 Genomes and ESP. This variant in the -2 splice acceptor site of intron 6 disrupts the reading frame and is predicted to undergo nonsense mediated decay (NMD). 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, PP4.

PVS1

This variant in the -2 splice acceptor site of IVS6 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). This variant breaks the splice site in IVS6 according to Splice AI (0.98 – splice-altering) and TraP (0.611, >97.5%ile, probably damaging).

PP4

This variant was documented 1 time in a patient with PAH deficiency defined as classic PKU (>1200 μmol/L Phe). Patient was reported to be compound heterozygous for the variant. PMID: 1563085

PM3

This variant was detected in trans with the pathogenic PAH variant p.Arg408Trp (1pt). PMID: 1563085

PM2

This variant is absent from population databases gnomAD, 1000 Genomes and ESP.

Curation History

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