Submissions for variant NM_000277.3(PAH):c.1056del (p.Glu353fs)

dbSNP: rs62507350

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV002259582	SCV002540145	pathogenic	Phenylketonuria	2022-06-12	reviewed by expert panel	curation	The c.1056del (p.Glu353AsnfsTer47) frameshift variant in PAH is predicted to terminate at codon 400 in exon 12, and would not undergo nonsense mediated-decay. This variant was reported in 4 patients within a Spanish cohort with mild and classic PKU. A defect in the synthesis or regeneration pathways 6R-BH4 was ruled out by analyzing urinary pterin levels as well as by measuring the dihydropteridine reductase activity (PMID 27121329). The variant was identified in trans with 4 pathogenic variants: p.Ala403Val, p.Ile306Val, c.1066-11G>A and p.Glu280Lys (PMID 27121329). This variant is absent from gnomAD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1_strong, PM2, PM3 very strong, and PP4 moderate.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088730	SCV000119312	not provided	not provided		no assertion provided	not provided
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001252101	SCV001427850	likely benign	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing