Submissions for variant NM_014363.6(SACS):c.9508C>T (p.Arg3170Ter)

gnomAD frequency: 0.00003  dbSNP: rs202199411

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000297710	SCV000329910	pathogenic	not provided	2024-10-22	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation, as the last 1410 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31980526, 23250129)
Athena Diagnostics	RCV000297710	SCV000843554	pathogenic	not provided	2024-09-27	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) This variant is not expected to cause loss of protein expression through nonsense-mediated decay. However, it disrupts a critical region of the protein, and therefore, is expected to severely disrupt its function. This variant has been identified in at least one individual with clinical features associated with this gene.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001223182	SCV001395319	pathogenic	Spastic paraplegia	2023-08-29	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs202199411, gnomAD 0.002%). 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: 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. ClinVar contains an entry for this variant (Variation ID: 280094). This premature translational stop signal has been observed in individual(s) with autosomal recessive spastic ataxia of Charlevoix-Saguenay (PMID: 23250129). This sequence change creates a premature translational stop signal (p.Arg3170*) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1410 amino acid(s) of the SACS protein.
Genome-Nilou Lab	RCV000411666	SCV002027630	pathogenic	Charlevoix-Saguenay spastic ataxia	2021-09-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000411666	SCV002819798	likely pathogenic	Charlevoix-Saguenay spastic ataxia	2022-12-24	criteria provided, single submitter	clinical testing	Variant summary: SACS c.9508C>T (p.Arg3170X) results in a premature termination codon and is predicted to cause a truncation of the encoded protein, which is a commonly known mechanism for disease. Although this premature termination is not expected to result in nonsense mediated decay, 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 250380 control chromosomes (gnomAD). c.9508C>T has been reported in the literature in at least one compound heterozygous individual affected with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay (Thiffault_2013). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed the variant since 2014: two classified the variant as likely pathogenic, and three as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV000411666	SCV004209895	pathogenic	Charlevoix-Saguenay spastic ataxia	2024-03-27	criteria provided, single submitter	clinical testing
PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research	RCV000411666	SCV005044539	pathogenic	Charlevoix-Saguenay spastic ataxia	2022-01-01	criteria provided, single submitter	research
Counsyl	RCV000411666	SCV000486037	likely pathogenic	Charlevoix-Saguenay spastic ataxia	2016-04-05	no assertion criteria provided	clinical testing