ClinVar

Description

Variant summary: PAH c.158G>A (p.Arg53His) results in a non-conservative amino acid change located in the ACT domain (IPR002912) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0017 in 251382 control chromosomes (gnomAD), predominantly at a frequency of 0.014 within the East Asian subpopulation in the gnomAD database, including 3 homozygotes. Ten homozygotes for c.158G>A have also been reported in individuals from the general Japanese population (Yamaguchi-Kabata_2019). The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) phenotype (0.0079), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.158G>A has been reported in the literature in (mostly East Asian) individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) and hyperphenylalaninemia (HPA) without strong evidence for causality (e.g. Park_1998, Liang_2014, Tao_2015, Zong_2018, Kuznetkova_2019, Lin_2019, Su_2019), with one report showing no clinical symptoms or signs of disease in 6 compound heterozygous patients identified during newborn screening and 1 homozygous parent, all of whom had blood Phe within the normal range while on a normal diet (e.g. Choi_2017). In multiple patients, the variant was reported in cis with another variant cited as pathogenic in ClinVar (e.g. Tao_2015, Odagiri_2021). In addition, the variant has been reported to co-occur with other pathogenic variants in PAH in individuals with PKU or HPA who were genotyped as either homozygotes or compound heterozygotes for other pathogenic variants that would be likely to explain the phenotype (e.g. Su_2019, Odagiri_2021). At least one publication reports experimental evidence evaluating an impact on protein function, where the variant protein had 79% enzymatic activity relative to the wild type control (Liang_2014). Nine ClinVar submitters have assessed the variant since 2014: five have classified the variant as of uncertain significance, two as likely benign, and two as benign. Based on the evidence outlined above, the variant was classified as benign.