Submissions for variant NM_000277.3(PAH):c.895T>C (p.Phe299Leu)

dbSNP: rs796064504

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000190378	SCV001250537	uncertain significance	Phenylketonuria	2019-06-09	reviewed by expert panel	curation	The c.895T>C (p.Phe299Leu) variant in PAH is reported as Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 208182); no further information is provided. At the time of review (5/25/19), the variant does not appear to be reported in the published literature and/or in the BioPKU database. The variant results in the substitution of a highly conserved Phenylalanine residue with Leucine; the amino acid substitution is predicted damaging by multiple lines of computational evidence e.g., predicted deleterious in SIFT, Polyphen2, Mutation Taster; REVEL= 0.96) (PP3). It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). Another missense variant at this site, p.Phe299Cys, has been previously reported Pathogenic/Likely Pathogenic by seven submitters in ClinVar (variant ID 613), where it was noted to be a recurrent allele among Norwegian PKU patients and have in-vitro data supporting that it impaired protein function. Another missense variant at this site, Phe299Ser, has also been reported in the BioPKU database (PAH0800). These reports of those variants support use of PM5.
Inserm U 954, Faculté de Médecine de Nancy	RCV000190378	SCV000243912	probable-pathogenic	Phenylketonuria		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.