PAH p.Phe410Ser

The NM_000277.3(PAH):c.1229T>C variant in PAH is a missense variant predicted to cause substitution of phenylalanine to serine at amino acid 410 (p.Phe410Ser). At least one patient with this variant displayed plasma phenylalanine concentration persistently above 120umol/L (2mg/dL) and sequencing of genes in the BH4 cofactor metabolism pathway to exclude a defect of BH4 cofactor metabolism which is highly specific for Phenylketonuria (PP4_moderate; PMIDs:26542770, 10679941). This variant has been detected in 2 individuals with Phenylketonuria. Of those individuals, both were compound heterozygous for the variant and distinct likely pathogenic p.P281L (parental testing was not reported) and pathogenic p.I306V (in trans) variants (PM3; PMID: 26542770). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0000008476 in European (non-Finnnish) population, which is lower than the ClinGen PAH Variant Curation Expert Panel threshold (<0.0002) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.992, which meets the threshold of 0.932, evidence that correlates with strong impact to PAH function (PP3_Strong). Two different missense variants, c.1229T>G (p.Phe410Cys) and c.1229T>G (p.Phe410Cys) are in the same codon have been classified as likely pathogenic for PAH deficiency by the ClinGen PAH Variant Curation Expert Panel (PM5). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2_supporting, PM3, PP3_strong, PP4_moderate, PM5. Version 2.0, 7/16/2024.