ClinVar

Description

Variant summary: SACS c.6000_6004delAAGAA (p.Arg2002CysfsX25) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 8e-06 in 250548 control chromosomes (gnomAD). The variant, c.6000_6004delAAGAA, has been reported in the literature, in homozygosity or compound heterozygous state, in multiple individuals affected with Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (Haskell_2018, Kara_2016, Vermeer_2008). These data indicate that the variant is likely to be associated with disease. Experimental evidence demonstrated the truncation or absence of the Sacsin protein in a patient derived cell line that was compound heterozygous for the variant of interest and another truncating SACS variant, in addition increased levels of reactive oxygen species, altered mitochondrial volume/morphology and a grossly abnormal vimentin cytoskeleton was also demonstrated (Bradshaw_2016, Duncan_2017). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.