The c.827T>G (p.Met276Arg) variant in PAH is absent from population databases and predicted damaging by in silico models. It is a novel missense change at an amino acid residue where different pathogenic missense changes have been reported (p.Met276Val is LP in ClinVar, p.Met276Lys is LP via PAH EP). It has been reported in individuals with phenylkeonuria in the literature, although a defect in the metabolism of BH4 has not been excluded as a cause for elevated phenylalanine in any of these patients (PMID: 23932990, 15300621). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM5, PP3.