PP4_met: This variant was reported in 1 patient with PAH deficiency (PMID: 27243974) and 1 patient with classic phenylketonuria (PMID: 30050108) 27243974, Yubero - This variant was documented in 1 patient with PAH deficiency. To compare the diagnostic yield obtained after NGS, patients were classified into two groups depending on the level of evidence supporting the suspicion and independently of the NGS analysis results. Group 1 (n = 81) included patients who presented with consistent clinical and biochemical data supporting their having an IEM studied in the panel. This patient with this variant was a part of this group. Tetrahydrobiopterin (BH4) deficiency was not excluded through a BH4 loading test, urinary pterin analysis and DHPR activity assay. 30050108, Li - This variant was documented in 1 patient with classic phenylketonuria. Tetrahydrobipterin (BH4) deficiency was not excluded through a BH4 loading test, urinary pterin analysis and DHPR activity although that data was collected if available.

PM3_strong: This variant was detected in trans with a likely pathogenic variant in 1 patient with PAH deficiency (PMID:27243974) and with a pathogenic variant in 1 patient with classic phenylketonuria (PMID: 30050108) 27243974, Yubero - This variant was detected in trans with the likely pathogenic PAH variant c.824C>T (1 submission in ClinVar) in one patient with PAH deficiency. The inheritance of all of the patients with genetic findings was checked regarding their progenitors. 30050108, Li - This variant was detected in trans with the pathogenic PAH variant p.Arg111Ter (7 submissions in ClinVar including PAH EP) in 1 patient with classic PKU. Parental analysis was performed to confirm compound heterozygosity.

PM4_met: Protein length changes as a result of an in-frame deletion in a non-repeat region.

PM2_met: This variant is absent from population databases gnomAD and ExAC.