Submissions for variant NM_014363.6(SACS):c.12923_12927del (p.Lys4308fs)

dbSNP: rs1057517294

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000409460	SCV000487057	likely pathogenic	Charlevoix-Saguenay spastic ataxia	2016-09-30	criteria provided, single submitter	clinical testing
Paris Brain Institute, Inserm - ICM	RCV000409460	SCV001451195	pathogenic	Charlevoix-Saguenay spastic ataxia		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002523875	SCV003444864	pathogenic	Spastic paraplegia	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys4308Serfs*21) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 272 amino acid(s) of the SACS protein. This variant is present in population databases (no rsID available, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with SACS-related conditions (PMID: 31493945, 33624863). ClinVar contains an entry for this variant (Variation ID: 371466). This variant disrupts a region of the SACS protein in which other variant(s) (p.Asn4549Asp) have been determined to be pathogenic (PMID: 15156359, 21507954). 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.
Ambry Genetics	RCV002523874	SCV003551091	likely pathogenic	Inborn genetic diseases	2020-12-03	criteria provided, single submitter	clinical testing	The c.12923_12927delAAGAA (p.K4308Sfs*21) alteration, located in exon 10 (coding exon 9) of the SACS gene, consists of a deletion of 5 nucleotides from position 12923 to 12927, causing a translational frameshift with a predicted alternate stop codon after 21 amino acids. This alteration occurs at the 3' terminus of the SACS gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 6% of the protein. Although the exact functional effect of this alteration is unknown, premature stop codons are typically deleterious in nature and truncating alterations downstream have been reported (Synofzik, 2013, Sun, 2019). Based on data from the Genome Aggregation Database (gnomAD) database, the SACS c.12923_12927delAAGAA alteration was observed in 0.003% (1/31,400) of total alleles studied. This alteration was reported homozygous in a 13 year old female patient with autosomal recessive spastic ataxia of Charlevoix-Saguenay. She had an unsteady ataxic gait, epilepsy, dysarthria, dysmetria, spasticity, clonus, polyneuropathy, and cerebellar atrophy. Her parents were consanguineous and there was a family history of other affected individuals (Arslan, 2020). Based on the available evidence, this alteration is classified as likely pathogenic.
Baylor Genetics	RCV000409460	SCV004209918	likely pathogenic	Charlevoix-Saguenay spastic ataxia	2024-02-29	criteria provided, single submitter	clinical testing
PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research	RCV000409460	SCV005044523	pathogenic	Charlevoix-Saguenay spastic ataxia	2022-01-01	criteria provided, single submitter	research