ClinVar Miner

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

dbSNP: rs1555203951
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV001044810 SCV001370862 pathogenic Phenylketonuria 2020-05-15 reviewed by expert panel curation 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
Labcorp Genetics (formerly Invitae), Labcorp RCV001044810 SCV001208629 pathogenic Phenylketonuria 2023-10-09 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 8 of the PAH gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with phenylketonuria (PMID: 22526846). This variant is also known as IVS8-2A>G. ClinVar contains an entry for this variant (Variation ID: 842394). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

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