ClinVar

Description

The p.Glu2548fs variant in SACS has not been previously reported in individuals with clinical features of autosomal recessive spastic ataxia of Charlevoix-Sague nay (ARSACS) or in large population studies. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at positi on 2548 and leads to a premature termination codon 7 amino acids downstream. Thi s premature termination codon occurs within the last exon of the gene (exon 10), and is more likely to escape nonsense mediated decay (NMD). Therefore, this var iant is predicted to result in a truncated protein that is 2025 amino acids shor ter and lacks several functional domains of the normal protein. Loss of function variants in the SACS gene, most of which occur in exon 10, have been reported i n several patients with ARSACS (Bouhlal 2011), and animal models support a loss of function mechanism of disease (Lariviere 2015). In summary, this variant meet s our criteria to be classified as pathogenic for ARSACS in an autosomal recessi ve manner (http://www.partners.org/personalizedmedicine/LMM).