Submissions for variant NM_014363.6(SACS):c.7273C>T (p.Arg2425Ter)

gnomAD frequency: 0.00001  dbSNP: rs145766983

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000599123	SCV000710509	pathogenic	not provided	2018-10-01	criteria provided, single submitter	clinical testing	The R2425X variant in the SACS gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function through protein truncation. The R2425X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret R2425X as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000704868	SCV000833839	pathogenic	Spastic paraplegia	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg2425*) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2155 amino acid(s) of the SACS protein. This variant is present in population databases (rs145766983, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with SACS-related conditions. ClinVar contains an entry for this variant (Variation ID: 370415). This variant disrupts a region of the SACS protein in which other variant(s) (p.Ile2949Phefs*4) have been determined to be pathogenic (PMID: 23250129). 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.
Genome-Nilou Lab	RCV000412060	SCV002027642	pathogenic	Charlevoix-Saguenay spastic ataxia	2021-09-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000412060	SCV002766371	likely pathogenic	Charlevoix-Saguenay spastic ataxia	2022-11-16	criteria provided, single submitter	clinical testing	Variant summary: SACS c.7273C>T (p.Arg2425X) results in a premature termination codon, which are commonly known mechanisms for disease. While the variant is not predicted to lead to nonsense-mediated decay, it does disrupt the last 2155 amino acids of the protein. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.2e-05 in 249774 control chromosomes. To our knowledge, no occurrence of c.7273C>T in individuals affected with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay and no experimental evidence demonstrating its impact on protein function have been reported. Four 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV000412060	SCV004202293	pathogenic	Charlevoix-Saguenay spastic ataxia	2022-08-20	criteria provided, single submitter	clinical testing
Counsyl	RCV000412060	SCV000485731	likely pathogenic	Charlevoix-Saguenay spastic ataxia	2016-02-04	no assertion criteria provided	clinical testing