ClinVar Miner

Submissions for variant NM_014363.6(SACS):c.6000_6004del (p.Arg2002fs)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001192590 SCV001360828 pathogenic Charlevoix-Saguenay spastic ataxia 2019-09-23 criteria provided, single submitter clinical testing 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.
Invitae RCV001232497 SCV001405059 pathogenic Spastic paraplegia 2020-06-01 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the SACS gene (p.Arg2002Cysfs*25). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2578 amino acids of the SACS protein. This variant is present in population databases (rs773754134, ExAC 0.002%). This variant has been observed in an individual affected with a SACS-related condition (PMID: 18465152). This variant disrupts the C-terminus of the SACS protein. Other variant(s) that disrupt this region (p.Arg3903*) have been determined to be pathogenic (PMID: 19892370, 21745802). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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