Submissions for variant NM_000277.3(PAH):c.1196_1199del (p.Val399fs)

dbSNP: rs199475603

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV002509214	SCV002818519	likely pathogenic	Phenylketonuria	2022-10-14	reviewed by expert panel	curation	The NM_000277.3(PAH):c.1196_1199del (p.Val399Glyfs*52) is a frameshift variant in exon 11 of 13 that may cause loss of function of the protein, however it is predicted to escape nonsense mediated decay. Exon 13 is considered a critical region because it (along with Exon 12) forms the oligomerization domain (residues 411-452), which is responsible for the dimerization and tetramerization of the enzyme, important for regulation of PAH activity (PVS1_Strong). At least one patient (Case 154 in PMID: 8807331) with this variant had classical PKU with a serum phenylalanine level of 2131 umol/L (above the >120 umol/L requirement). Exclusion of a defect of BH4 cofactor metabolism was not reported (PP4). Case 154 (PMID: 8807331) is compound heterozygous for c.196_1199del and Arg408Trp (ClinVar 577, classified Pathogenic by the PAH VCEP; PM3). This variant is absent from gnomAD v2.1.1 (PM2). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive phenylketonuria based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PVS1_strong, PP4, PM3, PM2. (PAH VCEP specifications version 1).
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088785	SCV000119372	not provided	not provided		no assertion provided	not provided