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 μmol/L (above the >120 μmol/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).