Submissions for variant NM_014363.6(SACS):c.12851_12854del (p.Glu4284fs)

dbSNP: rs786204628

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169401	SCV000220799	likely pathogenic	Charlevoix-Saguenay spastic ataxia	2014-10-14	criteria provided, single submitter	literature only
Neuberg Centre For Genomic Medicine, NCGM	RCV000169401	SCV004047188	likely pathogenic	Charlevoix-Saguenay spastic ataxia		criteria provided, single submitter	clinical testing	The frameshift variant c.12851_12854del (p.Glu4284AlafsTer23) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Glu4284AlafsTer23 variant is reported with the allele frequency of 0.0007966% in gnomAD and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Likely pathogenic. This variant causes a frameshift starting with codon Glutamic Acid 4284, changes this amino acid to Alanine residue, and creates a premature Stop codon at position 23 of the new reading frame, denoted p.Glu4284AlafsTer23. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Likely pathogenic.
Baylor Genetics	RCV000169401	SCV004210030	pathogenic	Charlevoix-Saguenay spastic ataxia	2023-02-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003588583	SCV004295460	pathogenic	Spastic paraplegia	2023-07-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu4284Alafs*23) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 296 amino acid(s) of the SACS protein. This variant is present in population databases (rs786204628, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with clinical features of SACS-related conditions (PMID: 19529988, 30460542). This variant is also known as c.12846_12850delAGAG. This variant disrupts a region of the SACS protein in which other variant(s) (p.Ser4496*) have been determined to be pathogenic (PMID: 15156359, 21507954; Invitae). 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.