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

dbSNP: rs1592945607

Total submissions: 2

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.
Center for Molecular Medicine, Children’s Hospital of Fudan University	RCV000850221	SCV000893127	pathogenic	Phenylketonuria	2019-03-08	no assertion criteria provided	clinical testing