Submissions for variant NM_014363.6(SACS):c.5125C>T (p.Gln1709Ter)

dbSNP: rs1057517311

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000412006	SCV000487079	pathogenic	Charlevoix-Saguenay spastic ataxia	2016-10-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001224413	SCV001396605	pathogenic	Spastic paraplegia	2023-03-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the SACS protein in which other variant(s) (p.Arg3903*) have been determined to be pathogenic (PMID: 9892370, 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. ClinVar contains an entry for this variant (Variation ID: 371484). This premature translational stop signal has been observed in individual(s) with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) (PMID: 18465152, 23497566). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Gln1709*) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2871 amino acid(s) of the SACS protein.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000412006	SCV001737756	pathogenic	Charlevoix-Saguenay spastic ataxia	2021-05-31	criteria provided, single submitter	clinical testing	Variant summary: SACS c.5125C>T (p.Gln1709X) 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 4e-06 in 247518 control chromosomes. c.5125C>T has been reported in the literature in individuals affected with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay (example, Vermeer_2008, Synofzik_2013). These data indicate that the variant is 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 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV000412006	SCV002027655	pathogenic	Charlevoix-Saguenay spastic ataxia	2021-09-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000412006	SCV004209989	pathogenic	Charlevoix-Saguenay spastic ataxia	2023-04-27	criteria provided, single submitter	clinical testing
PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research	RCV000412006	SCV005044623	pathogenic	Charlevoix-Saguenay spastic ataxia	2022-01-01	criteria provided, single submitter	research
Natera, Inc.	RCV000412006	SCV002086260	pathogenic	Charlevoix-Saguenay spastic ataxia	2020-06-27	no assertion criteria provided	clinical testing