PM3_strong: This variant was detected in trans with pathogenic variants in 4 classic PKU patients and 1 mild hyperphenylalaninemia (MHP) patient (PMID: 27121329, 15589814, 24941924, 10234516). 27121329 - This variant was detected in trans with the pathogenic PAH variant p.Arg243Gln in 1 patient with classic phenylketonuria, and parental analysis was performed to confirm compound heterozygosity. 15589814 - This variant was detected in trans with the pathogenic variant S349P in 1 patient with classic phenylketonuria. Parental analysis was not performed to confirm compound heterozygosity. 24941924 - This variant was detected in trans with the pathogenic PAH variant c.1045T>C (7 pathogenic submissions in ClinVar, 1 likely pathogenic) in 1 patient with classic phenylketonuria. This variant was also detected in trans with the pathogenic PAH variant c.782G>A in 1 patient with classic phenylketonuria. Familial segregation analysis was confirmed in most patients, but it was unclear whether segregation analysis was performed for these patients. 10234516 - This variant was detected in trans with the pathogenic PAH variant A403V in at least 1 patient with mild hyperphenylalanemia (MHP). Mendelian inheritance was confirmed when parental samples were available by DGGE or restriction enzyme digestion, but it is unclear whether parental analysis was performed to confirm compound heterozygosity in this case.

PP4_moderate: Detected in a patient with classical PKU. A defect in the synthesis or regeneration pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels as well as by measuring the dihydropteridine reductase activity. PMID: 27121329

PP3_met: predicted deleterious in SIFT, Polyphen2, mutationTaster, REVEL=0.96

PM2_met: Extremely low frequency in gnomAD (MAF=0.00003)

PM5_not met: P147L is interpreted as LP by PAH VCEP/ClinVar