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_000277.3(PAH):c.509+1G>A

CA229589

102707 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 87379187-178b-4950-9d77-c25303909e4e

Approved on: 2020-05-14

Published on: 2020-05-14

HGVS expressions

NM_000277.3:c.509+1G>A

NM_000277.3(PAH):c.509+1G>A

NC_000012.12:g.102866595C>T

CM000674.2:g.102866595C>T

NC_000012.11:g.103260373C>T

CM000674.1:g.103260373C>T

NC_000012.10:g.101784503C>T

NG_008690.1:g.56008G>A

NG_008690.2:g.96816G>A

NM_000277.1:c.509+1G>A

NM_000277.2:c.509+1G>A

NM_001354304.1:c.509+1G>A

NM_001354304.2:c.509+1G>A

ENST00000307000.7:c.494+1G>A

ENST00000549111.5:n.605+1G>A

ENST00000551988.5:n.530+10867G>A

ENST00000553106.5:c.509+1G>A

Pathogenic

PM2 PP4_Moderate PVS1

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

Variant c.509+1G>A in PAH was found in 1 Chinese patient with Phe levels >120 umol/L (PMID: 26322415). BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PP4-Moderate). This null variant, canonical +1 splice site, is in a gene where LOF is a known mechanism of disease. Exon skipping disrupts reading frame. Predicted to undergo NMD, not located in last exon or last 50bp of preliminary exon. Coding exon number 5 out of 13 coding exons (PVS1). Variant identified in 1/66684 European alleles in ExAC. This variant is present in European (non-Finnish) populations at a frequency of 0.00001 (Gnomad, ExAC) (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4-Moderate.

PM2

Variant identified in 1/66684 European alleles in ExAC. This variant is present in European (non-Finnish) populations at a frequency of 0.00001 (Gnomad, ExAC).

PP4_Moderate

Variant c.509+1G>A was found in 1 Chinese patient with Phe levels >120 umol/L (PMID: 26322415). BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes.

PVS1

This null variant canonical +1 splice site in a gene where LOF is a known mechanism of disease. Exon skipping disrupts reading frame. Predicted to undergo NMD, not located in last exon or last 50bp of preliminary exon. Coding exon number 5 out of 13 coding exons.

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