ClinVar Miner

Submissions for variant NM_014363.6(SACS):c.2182C>T (p.Arg728Ter)

dbSNP: rs752059006
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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000393719 SCV000329912 pathogenic not provided 2023-12-09 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation, as the last 3852 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30638817, 30271475, 25525159, 18465152, 26539891, 31589614, 23497566, 35130357, 34791078)
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000454220 SCV000537976 likely pathogenic Abnormal brain morphology criteria provided, single submitter research
CMT Laboratory, Bogazici University RCV000984212 SCV001548315 pathogenic Charlevoix-Saguenay spastic ataxia 2020-12-01 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000984212 SCV002027666 pathogenic Charlevoix-Saguenay spastic ataxia 2021-09-05 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV001848046 SCV002105012 pathogenic Hereditary spastic paraplegia 2016-12-12 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001859535 SCV002141331 pathogenic Spastic paraplegia 2023-10-28 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg728*) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 3852 amino acid(s) of the SACS protein. This variant is present in population databases (rs752059006, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with spastic ataxia of Charlevoix-Saguenay (PMID: 18465152, 23497566, 26539891, 30271475, 30638817). ClinVar contains an entry for this variant (Variation ID: 280095). This variant disrupts a region of the SACS protein in which other variant(s) (p.Gln4054*) have been determined to be pathogenic (PMID: 18465152, 27288452). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000984212 SCV002511803 pathogenic Charlevoix-Saguenay spastic ataxia 2022-04-05 criteria provided, single submitter clinical testing Variant summary: SACS c.2182C>T (p.Arg728X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.6e-05 in 250476 control chromosomes. c.2182C>T has been reported in the literature in multiple individuals affected with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay (example, Vermeer_2008, Synofzik_2013, Karaca_2015, Rezende_2019). These data indicate that the variant is very likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000984212 SCV003761331 likely pathogenic Charlevoix-Saguenay spastic ataxia 2023-01-25 criteria provided, single submitter curation The homozygous p.Arg728Ter variant in SACS was identified by our study in one individual with spastic ataxia. The p.Arg728Ter variant in SACS has been previously reported in at least 5 unrelated individuals with spastic ataxia of the Charlevoix-Saguenay type (PMID: 34476298, PMID: 35130357, PMID: 26539891, PMID: 30638817, PMID: 23497566, PMID: 18465152) but has been identified in 0.01% (1/10046) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs752059006). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of these 5 affected individuals, 2 were homozygotes (PMID: 18465152) and 3 were compound heterozygotes who carried variants of uncertain significance in trans (PMID: 23497566, PMID: 30638817, PMID: 26539891), which increases the likelihood that the p.Arg728Ter variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 280095) and has been interpreted as pathogenic or likely pathogenic by multiple submitters. This nonsense variant leads to a premature termination codon at position 728. Although this alteration occurs within the last 50bp of the second to last exon, it removes >50% of the protein and thus may lead to NMD. Loss of function of the SACS gene is an established disease mechanism of autosomal recessive spastic ataxia of the Charlevoix-Saguenay type. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive spastic ataxia of the Charlevoix-Saguenay type. ACMG/AMP Criteria applied: PVS1_Strong, PM2_Supporting, PM3 (Richards 2015).
Revvity Omics, Revvity RCV000984212 SCV003814524 likely pathogenic Charlevoix-Saguenay spastic ataxia 2022-03-31 criteria provided, single submitter clinical testing
Baylor Genetics RCV000984212 SCV004209912 pathogenic Charlevoix-Saguenay spastic ataxia 2024-03-22 criteria provided, single submitter clinical testing
PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research RCV000984212 SCV005044531 pathogenic Charlevoix-Saguenay spastic ataxia 2022-01-01 criteria provided, single submitter research
Counsyl RCV000984212 SCV001132279 likely pathogenic Charlevoix-Saguenay spastic ataxia 2014-01-02 no assertion criteria provided clinical testing
Natera, Inc. RCV000984212 SCV002086722 pathogenic Charlevoix-Saguenay spastic ataxia 2020-12-16 no assertion criteria provided clinical testing
Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology RCV000984212 SCV004812219 pathogenic Charlevoix-Saguenay spastic ataxia 2023-10-28 no assertion criteria provided research

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