ClinVar

This variant is classified as a variant of unknown significance because its contribution to spinocerebellar ataxia-19 (607346) has not been confirmed.

In a Dutch father and daughter with late-onset spinocerebellar ataxia, Duarri et al. (2012) identified a heterozygous c.1119G-A transition in the KCND3 gene, resulting in a met373-to-ile (M373I) substitution at a highly conserved residue. The mutation was initially found by direct sequencing of the KCND3 gene in 230 Dutch probands with ataxia in whom mutations in several known SCA genes were not identified. It was not present in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, or in 800 Dutch control chromosomes. The proband had ambiguous neurologic signs on testing at age 44 years, and later had no neurologic signs at age 52 years, consistent with being an asymptomatic carrier. He had a relevant family history, with both his father and a sister showing signs of the disorder. His father was more severely affected, with onset of progressive ataxic gait at age 55 years, dysarthria, and cerebellar atrophy on brain MRI. His sister had very mild gait impairment at age 64 years. Transfection of the M373I mutation into HeLa cells showed that the mutant protein had almost no cell surface expression, but rather accumulated in the endoplasmic reticulum, consistent with a trafficking defect. The mutant protein was more rapidly degraded compared to the wildtype protein, suggesting that it was misfolded. The trafficking and degradation defects could be rescued by coexpression with the active isoform of KCHIP2 (604661). Patch-clamp recordings showed that the mutant channel had decreased current activity (25% of controls).