ClinVar

Description

The H53Y variant has been published previously in association with congenital neutropenia (Smith et al., 2009). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). H53Y 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 in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (H53L/Q) and in nearby residues (L49P, C55S/Y, G56R, A57T/S/V) have been reported in the Human Gene Mutation Database in association with neutropenia (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.