ClinVar

Description

The PAH c.158G>A variant is predicted to result in the amino acid substitution p.Arg53His. This variant has been documented as a common PAH variant in the Chinese population, and has been associated with mild hyperphenylalanemia (mHPA) (Park et al. 1998. PubMed ID: 9452061; Song et al. 2005. PubMed ID: 16256386; Liang et al. 2014 PubMed ID: 24401910; Lin et al. 2019. PubMed ID: 30904546). In a recent study of individuals identified by newborn genetic screening, 16 patients were identified with mildly elevated phenylalanine and the c.158G>A (p.Arg53His) variant on the opposite allele (in trans) from a pathogenic or likely pathogenic PAH variant (Huang et al. 2022. PubMed ID: 35193651). It should be noted that this particular variant has been reported to have an allele frequency of >1% in eastern Asian populations, including 3 homozygous individuals (http://gnomad.broadinstitute.org/variant/12-103306579-C-T) and has been suggested to be a likely benign variant based on higher allele frequencies in East Asian populations (Choi et al. 2017. PubMed ID: 29032371). While these higher allele frequencies would normally be considered too common for a recessive, pathogenic variant, the p.Arg53His amino acid change has been shown to only decrease the activity of the PAH protein to ~80% of wild-type (Liang et al. 2014. PubMed ID: 24401910). Such a modest effect on protein activity and the mild clinical phenotype associated with this variant may be consistent with this somewhat high allele frequency, and it is possible this variant may be causative for MHPA but is less likely to be causative for mild to classic phenylketonuria. This variant is currently interpreted as benign, likely benign, or uncertain in the ClinVar database, with the PAH Variant Curation Expert Panel interpreting it as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/102601/). Based on the collective evidence, we also interpret the clinical significance of this variant as uncertain.