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.842+2T>A

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CA229813

614 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: e10d0c3d-b478-421d-9e3f-919a9e7ff2eb

Approved on: 2020-04-16

Published on: 2020-04-16

HGVS expressions

NM_000277.3:c.842+2T>A

NM_000277.3(PAH):c.842+2T>A

NM_000277.1:c.842+2T>A

NM_000277.2:c.842+2T>A

NM_001354304.1:c.842+2T>A

NM_001354304.2:c.842+2T>A

ENST00000307000.7:c.827+2T>A

ENST00000549247.6:n.601+2T>A

ENST00000553106.5:c.842+2T>A

ENST00000635477.1:n.3+2T>A

NC_000012.12:g.102852813A>T

CM000674.2:g.102852813A>T

NC_000012.11:g.103246591A>T

CM000674.1:g.103246591A>T

NC_000012.10:g.101770721A>T

NG_008690.1:g.69790T>A

NG_008690.2:g.110598T>A

Pathogenic

PVS1 PP4_Moderate PM2 PM3_Strong

Evidence Links 3

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.842+2T>A variant in PAH is a splice-site variant predicted to result in skipping of exon 8, leading to a frameshift, premature protein truncation, and NMD (PVS1). It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It is reported Pathogenic in Clinvar (ID 614). It has been reported among multiple patients with classic PKU, with BH4 deficiency formally excluded (PMID: 17557229; PMID: 21307867) (PP4_Moderate) and has been reported in trans with multiple Pathogenic and Likely Pathogenic mutations, including R111X (P, ClinGen); P281L (P, ClinGen); R413P (P, ClinGen); R243Q (P, ClinGen); R261Q (LP/P, ClinGen); R400T (unknown, ClinGen) (PMID: 17557229) (PM3_Strong). Classification: Pathogenic Supporting Criteria: PVS1, PM2, PM3_Strong, PP4_Moderate

PVS1

Null variant (canonical +2 splice site) in a gene where LOF is a known mechanism of disease

PP4_Moderate

Detected in multiple patients with classic PKU PMID: 17557229 Analysis of dihydropteridine reductase activity in red blood cells, biopterin loading test and/or pteridine analysis in urine PMID: 21307867.

Classic PKU (Phe>1200 umol/L) PubMed:17557229

Phe>0.18mM PubMed:21307867

PM2

Absent from controls in ExAC, gnomAD, 1000 Genomes, or ESP

Not observed in 104 controls from the same demographic PubMed:1349576

Not observed in 100 healthy controls (Phe<120 lmol/L) PubMed:17557229

PM3_Strong

Detected with: R111X (P, ClinGen); P281L (P, ClinGen); R413P (P, ClinGen); R243Q (P, ClinGen); R261Q (LP/P, ClinGen); R400T (unknown, ClinGen) Parental samples were available from a part of the families. PMID: 17557229 2.25 points

Detected in trans with: R111X (P, ClinGen) P281L (P, ClinGen) R413P (P, ClinGen) R243Q (P, ClinGen) R261Q (LP/P, ClinGen) R400T (unknown, ClinGen) PubMed:17557229

Curation History

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