Submissions for variant NM_014363.6(SACS):c.8793del (p.Lys2931fs)

dbSNP: rs767871841

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000519077	SCV000617740	pathogenic	not provided	2023-08-17	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation, as the last 1649 amino acids are replaced with 21 different amino acids, 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: 15486997, 31429931, 32606540, Sheetal_2021_article, 35499206)
Counsyl	RCV000674417	SCV000799750	likely pathogenic	Charlevoix-Saguenay spastic ataxia	2018-05-04	criteria provided, single submitter	clinical testing
Invitae	RCV000706287	SCV000835327	pathogenic	Spastic paraplegia	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys2931Asnfs*22) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1649 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 autosomal recessive spastic ataxia (PMID: 15486997). It has also been observed to segregate with disease in related individuals. This variant is also known as 6543delA. ClinVar contains an entry for this variant (Variation ID: 449517). This variant disrupts a region of the SACS protein in which other variant(s) (p.Arg3636*) have been determined to be pathogenic (PMID: 18465152). 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.
Athena Diagnostics Inc	RCV000519077	SCV001145350	pathogenic	not provided	2023-06-22	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 an critical region of the protein, and therefore, is expected to severely disrupt function. This variant has been identified in at least one individual with clinical features associated with this gene.
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000674417	SCV001149910	pathogenic	Charlevoix-Saguenay spastic ataxia	2018-04-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000674417	SCV001737737	pathogenic	Charlevoix-Saguenay spastic ataxia	2021-06-11	criteria provided, single submitter	clinical testing	Variant summary: SACS c.8793delA (p.Lys2931AsnfsX22) 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 250652 control chromosomes. c.8793delA has been reported in the literature as a homozygous mutation in several individuals affected with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay, including 2 affected siblings (e.g. Hara_2005, Shakya_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV000674417	SCV002027634	pathogenic	Charlevoix-Saguenay spastic ataxia	2021-09-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000674417	SCV004209946	pathogenic	Charlevoix-Saguenay spastic ataxia	2023-08-02	criteria provided, single submitter	clinical testing