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]

Link to SEPIO compliant JSON-LD document

Variant: NM_000277.3(PAH):c.510-2A>G

CA16020807

551658 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 66258a7c-6bc3-4f8b-bcbb-07ebbb24b5b4

HGVS expressions

NM_000277.3:c.510-2A>G

NM_000277.3(PAH):c.510-2A>G

NM_000277.1:c.510-2A>G

NM_000277.2:c.510-2A>G

NM_001354304.1:c.510-2A>G

NM_001354304.2:c.510-2A>G

ENST00000307000.7:c.495-2A>G

ENST00000549111.5:n.606-2A>G

ENST00000551988.5:n.531-2A>G

ENST00000553106.5:c.510-2A>G

NC_000012.12:g.102855334T>C

CM000674.2:g.102855334T>C

NC_000012.11:g.103249112T>C

CM000674.1:g.103249112T>C

NC_000012.10:g.101773242T>C

NG_008690.1:g.67269A>G

NG_008690.2:g.108077A>G

Pathogenic

PP4_Moderate PM2 PVS1

Evidence Links 3

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

This c.510-2A>G (aka IVS5-2A>G) variant in PAH has been observed in at least one patient with PAH deficiency; BH4 deficiency was ruled out (PMID: 26503515, 23932990, and 19915519). The variant is absent from controls in population databases. This variant in the -2 splice acceptor site of intron 5 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. The variant breaks the splice site in IVS5 according to computational models. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, and PP4_Moderate.

PP4_Moderate

This variant is observed in at least one patient with Phe >120 µmol/L in the Southern Chinese population. BH4 deficiency was ruled out using dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and a tetrahydrobiopterin loading test. PMID: 26503515, 23932990, and 19915519

PubMed:19915519

PubMed:26503515

PubMed:23932990

PM2

This variant is absent from controls in gnomAD, ExAC, and 1000 Genomes population databases.

PVS1

This variant in the -2 splice acceptor site of IVS5 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 IVS5 according to Splice AI (0.95- splice altering) and TraP (0.572, >97.5%ile, probably damaging).

Approved on: 2020-10-28

Published on: 2020-10-28

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