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

dbSNP: rs773754134

Total submissions: 5

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001232497	SCV001405059	pathogenic	Spastic paraplegia	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg2002Cysfs*25) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2578 amino acid(s) of the SACS protein. This variant is present in population databases (rs773754134, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with a SACS-related condition (PMID: 18465152). ClinVar contains an entry for this variant (Variation ID: 928541). This variant disrupts a region of the SACS protein in which other variant(s) (p.Arg3903*) have been determined to be pathogenic (PMID: 19892370, 21745802). 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.
Mendelics	RCV001192590	SCV002519000	pathogenic	Charlevoix-Saguenay spastic ataxia	2022-05-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001192590	SCV004209952	pathogenic	Charlevoix-Saguenay spastic ataxia	2024-03-10	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001192590	SCV002086246	pathogenic	Charlevoix-Saguenay spastic ataxia	2020-02-01	no assertion criteria provided	clinical testing