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.1199+1G>A

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229385

102556 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 279d077a-13e1-41b3-a6bc-5b2e85269209

Approved on: 2020-10-15

Published on: 2020-10-15

HGVS expressions

NM_000277.3:c.1199+1G>A

NM_000277.3(PAH):c.1199+1G>A

NM_000277.1:c.1199+1G>A

NM_000277.2:c.1199+1G>A

NM_001354304.1:c.1199+1G>A

NM_001354304.2:c.1199+1G>A

ENST00000307000.7:c.1184+1G>A

ENST00000549247.6:n.958+1G>A

ENST00000551114.2:n.861+1G>A

ENST00000553106.5:c.1199+1G>A

ENST00000635477.1:n.303+1G>A

ENST00000635528.1:n.714+1G>A

NC_000012.12:g.102843645C>T

CM000674.2:g.102843645C>T

NC_000012.11:g.103237423C>T

CM000674.1:g.103237423C>T

NC_000012.10:g.101761553C>T

NG_008690.1:g.78958G>A

NG_008690.2:g.119766G>A

Pathogenic

PVS1 PP4 PM2

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

This c.1199+1G>A variant in PAH was reported in 1 Czech patient with PAH deficiency (PMID: 23357515), although a defect in BH4 metabolism was not excluded. This variant is present in European (non-Finnish) populations at an extremely low frequency in gnomAD (MAF: 0.00001). This variant in the +1 splice donor site results in exon skipping, which disrupts the reading frame and is predicted to undergo nonsense mediated decay. 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, PP4.

PVS1

PVS1_met: This variant in the +1 splice donor site of IVS11 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). The exon is present in biologically-relevant transcripts. This variant breaks the splice site in IVS11 according to Splice AI (0.64 - splice-altering) and TraP (0.941, >99%ile, probably damaging).

PP4

PP4_met: This variant was documented in 1 patient with HPA (PMID: 23357515). 23357515, Réblová - This variant was documented in 1 Czech patient with HPA. The paper defined HPA in their intro: "HPA patients can be classified based on their off-diet diagnostic plasma Phe levels as classical PKU (Phe above 1200 μmol/L), mild PKU (Phe between 600 and 1200 μmol/L) or non-PKU HPA (Phe between 120 and 600 μmol/L)."

PubMed:23357515

PM2

PM2_met: This variant is present in European (non-Finnish) populations at an extremely low frequency in gnomAD (MAF: 0.00001).

Curation History

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