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_000277.1:c.1200-2A>G

CA16020965

862570 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: d672dbe7-a194-4f0f-a06b-2c83e1d553bb

Approved on: 2020-08-10

Published on: 2021-09-26

HGVS expressions

NM_000277.1:c.1200-2A>G

ENST00000553106.6:c.1200-2A>G

ENST00000307000.7:c.1185-2A>G

ENST00000549247.6:n.959-2A>G

ENST00000551114.2:n.862-2A>G

ENST00000553106.5:c.1200-2A>G

ENST00000635477.1:n.304-2A>G

ENST00000635528.1:n.715-2A>G

NM_000277.2:c.1200-2A>G

NM_001354304.1:c.1200-2A>G

NM_000277.3:c.1200-2A>G

NM_001354304.2:c.1200-2A>G

NC_000012.12:g.102840517T>C

CM000674.2:g.102840517T>C

NC_000012.11:g.103234295T>C

CM000674.1:g.103234295T>C

NC_000012.10:g.101758425T>C

NG_008690.1:g.82086A>G

NG_008690.2:g.122894A>G

Pathogenic

PP4_Moderate PM2 PVS1

PM3

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1200-2A>G variant in PAH is a null variant (canonical - 2 splice site); Loss of function is a known mechanism of disease, exon skipping disrupts reading frame and is predicted to undergo NMD (not located in last 50bp of preliminary exon). Coding exon 12/13 is present in biologically-relevant transcript. This variant has been reported in 2 individuals with PKU (BH4 deficiency excluded, PMID: 21147011, 24301756). This variant is absent in population databases. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4_Moderate.

PP4_Moderate

IVS11-2A>G is seen in 2 PKU patients. BH4 deficiency was ruled out in 1 patient with assessment of PAH gene and genes of the BH4 synthesis/recycling pathways (PTS and QDPR. PMID: 21147011, PMID: 24301756

Forty Iranian patients with clinical and biochemically confirmed PKU were enrolled. The exons were sequenced directly. IVS11-2A>G was identified on 2 alleles in 1 patient with classic PKU (1620 uM pre-treatment Phe level). PubMed:24301756

588 hyperphenylalaninemic patients were investigated. Assessment included PAH gene and genes of the BH4 synthesis/recycling pathways (PTS and QDPR). IVS11-2A>G is seen in 1 PKU patient. PubMed:21147011

PM2

Absent from ExAC, gnomAD, 1000G, ESP

PVS1

Null variant (canonical - 2 splice site) where LOF is a known mechanism of disease, exon skipping disrupts reading frame, and is predicted to undergo NMD (not located in last 50bp of preliminary exon). Coding exon 12/13 is present in biologically-relevant transcript.

PM3

Detected with IVS10-7C>A (not in ClinVar, PAH EP=LP)

Detected with IVS10-7C>A (not in ClinVar, PAH EP = VUS) PubMed:21147011

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