ClinVar

Description

The N772H variant in the AR gene has been reported previously as N771H using alternate nomenclature in association with partial androgen insensitivity, and its presence is consistent with the diagnosis in this patient. This variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The N772H variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. The N772H variant is located within the ligand binding domain. In silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, a functional study has shown that this variant (reported as N771H using alternate nomenclature) significantly decreased the dose-response of dihydrotestosterone-induced transactivation activity (Cai et al., 2012). Missense variants in nearby residues (P767A, P767S, D768Y, D768V, D768E, L769V, L769M, L769P, E773G, E773A, Y774H, Y774C, R775C, R775H, R775L) have been reported in the Human Gene Mutation Database in association with Androgen insensitivity syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we consider this variant to be pathogenic.