Total submissions: 14
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
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, |
RCV000454220 | SCV000537976 | likely pathogenic | Abnormal brain morphology | criteria provided, single submitter | research | ||
CMT Laboratory, |
RCV000984212 | SCV001548315 | pathogenic | Charlevoix-Saguenay spastic ataxia | 2020-12-01 | criteria provided, single submitter | clinical testing | |
Genome- |
RCV000984212 | SCV002027666 | pathogenic | Charlevoix-Saguenay spastic ataxia | 2021-09-05 | criteria provided, single submitter | clinical testing | |
Genome Diagnostics Laboratory, |
RCV001848046 | SCV002105012 | pathogenic | Hereditary spastic paraplegia | 2016-12-12 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
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, |
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, |
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, |
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 |
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, |
RCV000984212 | SCV002086722 | pathogenic | Charlevoix-Saguenay spastic ataxia | 2020-12-16 | no assertion criteria provided | clinical testing | |
Department of Biotechnology and Genetic Engineering, |
RCV000984212 | SCV004812219 | pathogenic | Charlevoix-Saguenay spastic ataxia | 2023-10-28 | no assertion criteria provided | research |