Submissions for variant NM_014363.6(SACS):c.9346_9354dup (p.Lys3116_Pro3118dup)

dbSNP: rs2137584629

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
3billion	RCV002052090	SCV002318526	likely pathogenic	Charlevoix-Saguenay spastic ataxia	2022-03-22	criteria provided, single submitter	clinical testing	Inframe insertion located in a nonrepeat region: predicted to change the length of the protein and disrupt normal protein function. This variant has been reported as pathogenic (PMID:27133561). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual(PMID: 27133561). It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002552344	SCV003442025	uncertain significance	Spastic paraplegia	2022-04-12	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has been observed in individual(s) with spastic paraplegia (PMID: 27133561). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This variant, c.9346_9354dup, results in the insertion of 3 amino acid(s) of the SACS protein (p.Lys3116_Pro3118dup), but otherwise preserves the integrity of the reading frame.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004699656	SCV005204251	uncertain significance	not specified	2024-06-27	criteria provided, single submitter	clinical testing	Variant summary: SACS c.9346_9354dupAAGCTGCCT (p.Lys3116_Pro3118dup) results in an in-frame duplication that is predicted to duplicate three amino acids into the encoded protein. The variant was absent in 250610 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9346_9354dupAAGCTGCCT has been reported in the literature in compound heterozygous twins affected with spastic paraplegia (e.g. Armour_2016). 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. The following publication have been ascertained in the context of this evaluation (PMID: 27133561). ClinVar contains an entry for this variant (Variation ID: 1526070). Based on the evidence outlined above, the variant was classified as uncertain significance.
Neuberg Centre For Genomic Medicine, NCGM	RCV002052090	SCV006077059	uncertain significance	Charlevoix-Saguenay spastic ataxia	2024-02-01	criteria provided, single submitter	clinical testing	The observed inframe insertion variant sc.9346_9354dup(p.Lys3116_Pro3118dup) in SACS gene has been reported previously in in compound heterozygous state in an individual with spastic ataxia of Charlevoix-Saguenay (Armour CM, et al., 2016).