Submissions for variant NM_014363.6(SACS):c.7276C>T (p.Arg2426Ter)

dbSNP: rs786204750

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169603	SCV000221123	likely pathogenic	Charlevoix-Saguenay spastic ataxia	2015-02-06	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000734960	SCV000863142	pathogenic	not provided	2018-08-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169603	SCV001737679	pathogenic	Charlevoix-Saguenay spastic ataxia	2021-06-10	criteria provided, single submitter	clinical testing	Variant summary: SACS c.7276C>T (p.Arg2426X) 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 was absent in 250002 control chromosomes. c.7276C>T has been reported in the literature in individuals affected or suspected to be affected with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay (e.g. Baets_2010, Lee_2014, Shakya_2019). These data indicate that the variant may be 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. Both laboratories cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV000169603	SCV002027641	pathogenic	Charlevoix-Saguenay spastic ataxia	2021-09-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001850407	SCV002195463	pathogenic	Spastic paraplegia	2023-12-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg2426*) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2154 amino acid(s) of the SACS protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of spastic paraplegia (PMID: 20876471). ClinVar contains an entry for this variant (Variation ID: 189175). 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.
Baylor Genetics	RCV000169603	SCV004202316	pathogenic	Charlevoix-Saguenay spastic ataxia	2024-01-24	criteria provided, single submitter	clinical testing
PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research	RCV000169603	SCV005044571	pathogenic	Charlevoix-Saguenay spastic ataxia	2022-01-01	criteria provided, single submitter	research
Fulgent Genetics, Fulgent Genetics	RCV000169603	SCV005634282	likely pathogenic	Charlevoix-Saguenay spastic ataxia	2024-02-21	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000169603	SCV002086221	pathogenic	Charlevoix-Saguenay spastic ataxia	2021-09-15	no assertion criteria provided	clinical testing