Submissions for variant NM_014363.6(SACS):c.10136T>G (p.Leu3379Ter)

gnomAD frequency: 0.00001  dbSNP: rs1057517250

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000412241	SCV000486982	likely pathogenic	Charlevoix-Saguenay spastic ataxia	2016-09-19	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000992769	SCV001145303	pathogenic	not provided	2019-07-23	criteria provided, single submitter	clinical testing	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.
Genome-Nilou Lab	RCV000412241	SCV002027629	pathogenic	Charlevoix-Saguenay spastic ataxia	2021-09-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001861393	SCV002143921	pathogenic	Spastic paraplegia	2023-12-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu3379*) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1201 amino acid(s) of the SACS protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with SACS-related conditions (PMID: 29968200). ClinVar contains an entry for this variant (Variation ID: 371410). This variant disrupts a region of the SACS protein in which other variant(s) (p.Tyr4538*) have been determined to be pathogenic (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.
Variantyx, Inc.	RCV000412241	SCV002754536	pathogenic	Charlevoix-Saguenay spastic ataxia	2022-11-07	criteria provided, single submitter	clinical testing	This is a nonsense variant in the SACS gene (OMIM 604490). Biallelic pathogenic variants in this gene have been associated with autosomal recessive spastic ataxia of the Charlevoix-Saguenay type (ARSACS). This variant introduces a premature termination codon in exon 10 out of 10. It is expected to disrupt the C-terminal region of the protein and result in loss of function, which is a known disease mechanism for SACS in this disorder (PMID: 21507954, 25260547). Additionally, multiple loss-of-function variants downstream of this position have also been reported as pathogenic (PMID: 18465152, 18604465, 20798953, 24180463, 26288984) (PVS1). This variant has been reported in the compound heterozygous state in at least 1 affected individual (PMID: 29968200) (PM3_Supporting). This variant has a 0.001471% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/), which is lower than expected for the prevalence of ARSACS (PM2_Supporting). Based on current evidence, this variant is interpreted as pathogenic for autosomal recessive ARSACS.
Fulgent Genetics, Fulgent Genetics	RCV000412241	SCV002805742	pathogenic	Charlevoix-Saguenay spastic ataxia	2021-08-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000412241	SCV004209928	likely pathogenic	Charlevoix-Saguenay spastic ataxia	2023-08-21	criteria provided, single submitter	clinical testing
PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research	RCV000412241	SCV005044656	pathogenic	Charlevoix-Saguenay spastic ataxia	2022-01-01	criteria provided, single submitter	research