ClinVar

Description

The I296N variant has previously been reported in association with classic PKU, however additional information regarding additional PAH variants identified in these patients was not reported (Guldberg et al., 1998; Zschocke et al., 1999; Acosta et al., 2001). This variant has also been reported in an individual with BH4-unresponsive phenylalanine hydroxylase deficiency who was also heterozygous for two additional pathogenic missense variants in the PAH gene, although the phase of these variants was not determined (Sarkissian et al., 2012). The I269N variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and is expected to distort ionic interactions with L-Phenylalanine at the substrate binding site of the PAH protein (Pey et al., 2007). In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, the I269N variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.