Submissions for variant NM_000277.3(PAH):c.916del (p.Ile306fs)

dbSNP: rs281865456

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000106377	SCV001146756	pathogenic	Phenylketonuria	2019-09-29	reviewed by expert panel	curation	The c.916delA (p.Ile306Leufs) in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 120296); the collection method is stated as 'literature only' and no further information is provided. With respect to the published literature, it has been previously reported in one Korean proband with classic PKU (defined by the authors as plasma phenylalanine levels > 1200umol/L); BH4 deficiency was formally excluded via urinary pterin analysis and DHPR assays (PMID: 18985011) (PP4_Moderate). The proband was said to be heterozygous for the variant and also harbor the known pathogenic allele (see ClinVar ID 608) c.143T>C (p.Leu48Ser) variant; while the manuscript stated that samples from proband's family members were collected, it does not appear to specify whether the phase of the variants was confirmed via parental testing. Thus, at this point, PM3 cannot be applied with full confidence. The sequence change results in a frameshift variant which occurs in exon 9 of 13 in the in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (see PMID: 30192042) (PVS1). It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2).
Inserm U 954, Faculté de Médecine de Nancy	RCV000106377	SCV000143877	probable-pathogenic	Phenylketonuria		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.