This variant is classified as a variant of unknown significance because its contribution to congenital hydrocephalus due to aqueductal stenosis (see, e.g., 236635) has not been confirmed.
In a 23-year-old Caucasian woman with congenital hydrocephalus due to aqueductal stenosis, Allocco et al. (2019) identified compound heterozygous missense variants in the ATP1A3 gene: a c.55G-A transition (c.55G-A, NM_152296) in exon 2, resulting in an arg19-to-cys (R19C) substitution inherited from the unaffected mother, and a c.1387G-A transition in exon 11, resulting in an arg463-to-cys (R463C; 182350.0023) substitution inherited from the unaffected father. The variants were identified by whole-exome sequencing and confirmed by Sanger sequencing. The R19C variant was present in the heterozygous state at a low frequency in gnomAD (6.4 x 10(-5)). Both variants occurred at conserved residues and were predicted to have disruptive effects on protein stability, although functional studies of the variants and studies of patient cells were not performed. The patient had multiple brain malformations, including open schizencephaly, type 1 Chiari malformation, and dysgenesis of the corpus callosum. Clinical details were limited, but she was noted to have learning disabilities. The authors postulated that dysregulation of neural development may be the pathogenesis of the disorder in this patient.
