Background: The accurate interpretation of sequence variation is critical for successful molecular diagnoses. It is also fundamental to the accurate diagnosis and treatment of phenylketonuria (PKU). This study aims to evaluate the significance of the c.158G>A (p.Arg53His) variant in the PAH gene, which was previously reported to be a pathogenic mutation that results in decreased phenylalanine hydroxylase enzyme activity in hyperphenylalaninemia (HPA) patients.
Methods: Seven unrelated Korean patients with HPA genotyped with the c.158G>A variant were included in this study. The variant c.158G>A was classified by the standards and guidelines for the interpretation of sequence variants by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
Results: By both directly collecting genetic data and comprehensively reviewing the existing literature, we found that this variant is more appropriately classified as "Likely benign" rather than pathogenic. The allele's frequency is 2.57% in the general Korean population, which was greater than expected for phenylketonuria. This variant was observed to be homozygous in healthy subjects and was also observed in cis with other pathogenic variants. It is common in East Asian populations (especially in Koreans) compared to Western populations. There is a possibility that it causes decreased enzyme activity without leading to the full pathology of phenylketonuria.
Conclusions: This study expands our understanding of the consequences of variation in PAH and its relationship to HPA.
Keywords: PAH; hyperphenylalaninemia; phenylalanine; phenylketonuria.