ClinVar

Description

The R81W variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). R81W 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. However, this substitution occurs at a position within the Peptidase S1 domain that is not conserved, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in the same residue (R81P) and in nearby residues (R78H, V80G, V82M, V83D, L84P, G85R/E) 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, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.