ClinVar Miner

Submissions for variant NM_014363.6(SACS):c.10906C>T (p.Arg3636Ter) (rs780247476)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000192438 SCV000248779 pathogenic Charlevoix-Saguenay spastic ataxia 2014-08-07 criteria provided, single submitter clinical testing
Counsyl RCV000192438 SCV000485801 likely pathogenic Charlevoix-Saguenay spastic ataxia 2016-02-19 criteria provided, single submitter clinical testing
Invitae RCV000633059 SCV000754271 pathogenic Spastic paraplegia 2019-10-08 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the SACS gene (p.Arg3636*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 944 amino acids (~20%) of the SACS protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in combination with another SACS variant in a single family affected with early-onset cerebellar ataxia (PMID: 18465152). ClinVar contains an entry for this variant (Variation ID: 212108). A different truncation (p.Arg3903*) that lies downstream of this variant has been determined to be pathogenic (PMID: 19892370, 21745802). This suggests that deletion of this region of the SACS protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000192438 SCV001338267 pathogenic Charlevoix-Saguenay spastic ataxia 2020-02-14 criteria provided, single submitter clinical testing Variant summary: SACS c.10906C>T (p.Arg3636X) results in a premature termination codon in the last exon, that is not expected to result in nonsense mediated decay (NMD), but is predicted to cause a large truncation of the encoded protein. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.11374C>T (p.Arg3792X)). The variant allele was found at a frequency of 1.2e-05 in 250508 control chromosomes (gnomAD). The variant, c.10906C>T, has been reported in the literature in multiple compound heterozygous- and a homozygous individual affected with Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (Vermeer_2008, Walsh_2017, Sun_2019, Tsugawa_2015). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and laboratories classified the variant as pathogenic (1x) / likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic.

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