ClinVar

Description

Variant summary: PAH c.934G>C (p.Gly312Arg) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251274 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.934G>C has been reported in the literature in at-least one individual affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example: Bashyam_2014). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 24130151). Other variants affecting the same residue (p.Gly312Val, p.Gly312Cys, p.Gly312Asp) have been classified pathogenic or likely pathogenic in ClinVar (CV IDs 1458264, 446506, 102901). One submitter (ClinGen PAH Variant Curation Expert Panel) has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.