Submissions for variant NM_014363.6(SACS):c.11374C>T (p.Arg3792Ter)

dbSNP: rs565203731

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000411243	SCV000699370	pathogenic	Charlevoix-Saguenay spastic ataxia	2017-02-23	criteria provided, single submitter	clinical testing	Variant summary: The SACS c.11374C>T (p.Arg3792X) variant results in a premature termination codon, predicted to cause a truncated or absent SACS protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Mutation taster predicts a damaging outcome for this variant. This variant is absent in 121060 control chromosomes while it was reported in multiple ARSACS patients indicating causality. In addition a clinical diagnostic laboratory classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic.
Paris Brain Institute, Inserm - ICM	RCV000411243	SCV001451191	pathogenic	Charlevoix-Saguenay spastic ataxia		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001310676	SCV001500568	pathogenic	not provided	2020-10-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000411243	SCV002027623	pathogenic	Charlevoix-Saguenay spastic ataxia	2021-09-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000411243	SCV004209977	pathogenic	Charlevoix-Saguenay spastic ataxia	2024-03-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003766121	SCV004670737	pathogenic	Spastic paraplegia	2023-11-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg3792*) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 788 amino acid(s) of the SACS protein. This variant is present in population databases (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with clinical features of hereditary spastic paraplegia (PMID: 18569450, 31743419, 33624863). ClinVar contains an entry for this variant (Variation ID: 370283). This variant disrupts a region of the SACS protein in which other variant(s) (p.Asn4549Asp) have been determined to be pathogenic (PMID: 15156359, 21507954). 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.
PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research	RCV000411243	SCV005061955	pathogenic	Charlevoix-Saguenay spastic ataxia	2022-01-01	criteria provided, single submitter	research
Counsyl	RCV000411243	SCV000485547	likely pathogenic	Charlevoix-Saguenay spastic ataxia	2016-01-05	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000411243	SCV002086152	pathogenic	Charlevoix-Saguenay spastic ataxia	2020-09-11	no assertion criteria provided	clinical testing