Variant: NM_000277.3(PAH):c.913-2A>G

842394 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

UUID: fc07c466-8fc8-4575-a4ac-d5144a1b7776

Approved on: 2020-05-15

Published on: 2020-05-15

HGVS expressions

NM_000277.3:c.913-2A>G
NM_000277.3(PAH):c.913-2A>G

Pathogenic

• Met criteria codes: PM2 PM3_Strong PVS1_Strong PP4_Moderate

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.913-2A>G variant in PAH is a canonical splice-site variant predicted to lead to skipping of exon 9 (PVS1_Strong). It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It has been reported in the published literature twice: in one proband with abnormal blood Phe levels and BH4 deficiency excluded by urinary pterin analysis (PMID: 19394257), but no further information provided; and in three probands with abnormal blood Phe levels and BH4 deficiency excluded by urinary pterin analysis (PMID: 22526846), in confirmed trans with the known pathogenic p.R408Q mutation (Pathogenic per PAH VCEP), the known pathogenic p.R158Q mutation (Pathogenic per PAH VCEP), and the known pathogenic IVS12+1G>A mutation (Pathogenic per PAH VCEP) (PP4_Moderate) (3 points total; PM3_Strong). It is also classified Pathogenic by one lab in ClinVar (variant ID 842394). Classification: Pathogenic Supporting Criteria: PVS1_Strong; PM3_Strong; PM2; PP4_Moderate

Met criteria codes

• PM2: It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2).
• PM3_Strong: Confirmed trans with the known pathogenic p.R408Q mutation (Pathogenic per PAH VCEP), the known pathogenic p.R158Q mutation (Pathogenic per PAH VCEP), and the known pathogenic IVS12+1G>A mutation (Pathogenic per PAH VCEP) (3 points total; PM3_Strong).
• PVS1_Strong: The c.913-2A>G variant in PAH is a canonical splice-site variant predicted to lead to skipping of exon 9 (PVS1_Strong).
• PP4_Moderate: It has been reported in the published literature twice: in one proband with abnormal blood Phe levels and BH4 deficiency excluded by urinary pterin analysis (PMID: 19394257) (PP4_Moderate), but no further information provided; and in three probands with abnormal blood Phe levels and BH4 deficiency excluded by urinary pterin analysis (PMID: 22526846), in confirmed trans with the known pathogenic p.R408Q mutation (Pathogenic per PAH VCEP), the known pathogenic p.R158Q mutation (Pathogenic per PAH VCEP), and the known pathogenic IVS12+1G>A mutation (Pathogenic per PAH VCEP) (3 points total; PM3_Strong).