ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1200-2A>C (rs1592945607)

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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 RCV000850221 SCV001370801 pathogenic Phenylketonuria 2020-04-09 reviewed by expert panel curation The c.1200-2A>C variant in PAH is a null variant (canonical +/- 1 or 2 splice sites) in a gene where LOF is a known mechanism of disease, exon skipping disrupts reading frame, and is predicted to undergo NMD. Coding exon 12 is present in biologically-relevant transcript (PVS1). It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It has been previously reported in two Ugyur probands (PMID: 31355225) with classic PKU; BH4 deficiency was formally excluded by urinary pterin analysis (PP4_Moderate). Both cases were compound heterozygous for the variant (confirmed by parental testing): one carried it in trans with the p.A104D variant (known pathogenic per PAH ClinGen working group) and the other in trans with p.P147L variant (Likely Pathogenic per PAH ClinGen working group) (PM3_Strong). It is reported pathogenic in Clinvar (ID 625286) as a de novo variant by one lab, in a case with PKU; no further information is given.
The Molecular Genetic Diagnosis Center, Children’s Hospital of Fudan University RCV000850221 SCV000893127 pathogenic Phenylketonuria 2019-03-08 no assertion criteria provided clinical testing

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