ClinVar Miner

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

dbSNP: rs786204628
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Total submissions: 4
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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 Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine 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
Invitae 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.

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