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

gnomAD frequency: 0.00001  dbSNP: rs755824618

Total submissions: 4

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001387163	SCV001587722	pathogenic	Spastic paraplegia	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys1715*) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2865 amino acid(s) of the SACS protein. This variant is present in population databases (rs755824618, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with SACS-related conditions (PMID: 18465152). ClinVar contains an entry for this variant (Variation ID: 917652). This variant disrupts a region of the SACS protein in which other variant(s) (p.Arg4325*) have been determined to be pathogenic (PMID: 16944349, 21993619, 23280630). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV001174760	SCV002027654	pathogenic	Charlevoix-Saguenay spastic ataxia	2021-09-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001174760	SCV004209974	pathogenic	Charlevoix-Saguenay spastic ataxia	2024-02-05	criteria provided, single submitter	clinical testing