ClinVar Miner

Submissions for variant NM_014363.6(SACS):c.5143A>T (p.Lys1715Ter)

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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 RCV001174760 SCV001338077 pathogenic Charlevoix-Saguenay spastic ataxia 2021-05-13 criteria provided, single submitter clinical testing Variant summary: SACS c.5143A>T (p.Lys1715X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2.5e-05 in 243814 control chromosomes. c.5143A>T has been reported in the literature in a compound heterozygous individual affected with Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (Vermeer_2008). Experimental evidence demonstrated the truncation (or absence) of the Sacsin protein in a cell line derived from this compound heterozygous patient; in addition increased levels of reactive oxygen species, altered mitochondrial volume/morphology and a grossly abnormal vimentin cytoskeleton were also revealed, and these alterations were similar to those observed in sacsin-deficient cells and in other patient derived cell lines (Bradshaw_2016, Duncan_2017). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV001387163 SCV001587722 pathogenic Spastic paraplegia 2020-07-02 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the SACS gene (p.Lys1715*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2865 amino acids of the SACS protein. This variant is present in population databases (rs755824618, ExAC 0.01%). This variant has been observed in individual(s) with SACS-related conditions (PMID: 18465152). This variant disrupts the C-terminus of the SACS protein. Other variant(s) that disrupt this region (p.Leu4303*, p.Glu4309*, p.Arg4325*, and p.Phe4352Leufs*11) have been determined to be pathogenic and/or reported in individuals affected with autosomal recessive spastic ataxia of Charlevoix-Saguenay (PMID: 23497566, 26288984, 16944349, Invitae). 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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