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PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency. ExAC MAF=0.00019.; PP3: Predicted deleterious in SIFT, Polyphen-2, MutationTaster. REVEL=0.939; PS3: 2% mutant enzyme activity in BioPKU; PP4_Moderate: Detected in at least 3 patients with PAH deficiency. BH4 deficiency ruled out in 1 patient. (PMID:1307609; PMID:10429004; PMID:9634518); PM3_Strong: Detected with 3 pathogenic/likely pathogenic variants (PMID:14681498; PMID:23430918). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PS3, PP4_Moderate, PM3_Strong).
Met criteria codes
Detected in at least 3 patients with PAH deficiency. BH4 deficiency ruled out in 1 patient.
R158W was detected. In all patients, hyperphenylalaninemia had been detected by national mass screening programs, and PAH deficiency had been assessed after exclusion of a defect in tetrahydrobiopterin metabolism.
A novel Arg158 (CGG)-to-Trp158 (TGG) mutation was identified in exon 5 of the PAH gene in a Chinese PKU patient.
In case 2, P407S (VarID102568, clinical significance not provided) was detected in one allele and R158W in the other allele.
Extremely low frequency. ExAC MAF=0.00019.
2% mutant enzyme activity in BioPKU
Approved on: 2018-08-10
Published on: 2019-04-06
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