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Please note this is a beta version of the ClinGen Evidence Repository. This resource is intended to provide access to variant level evidence used and applied by ClinGen Variant Curation Expert Panels in the classification of variants. In this beta version, the evidence is limited to curation notes and referenced literature (PMIDs).

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Criteria Specification: CSpec Registry PDF

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

CA16020807

551658 (ClinVar)

Gene: PAH
Condition: phenylketonuria
Inheritance Mode: Autosomal recessive inheritance

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

Met criteria codes 3
PVS1 PP4_Moderate PM2

Expert Panel

Evidence Links 3

Evidence submitted by expert panel
PAH 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.
Met criteria codes
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).
PP4_Moderate
This variant is observed in at least one patient with Phe >120 ┬Ámol/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

PM2
This variant is absent from controls in gnomAD, ExAC, and 1000 Genomes population databases.
Approved on: 2020-10-28
Published on: 2020-10-28
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