ClinVar Genomic variation as it relates to human health
NM_014363.6(SACS):c.2182C>T (p.Arg728Ter)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_014363.6(SACS):c.2182C>T (p.Arg728Ter)
Variation ID: 280095 Accession: VCV000280095.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q12.12 13: 23353788 (GRCh38) [ NCBI UCSC ] 13: 23927927 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 6, 2016 Apr 15, 2024 Oct 28, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_014363.6:c.2182C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_055178.3:p.Arg728Ter nonsense NM_001278055.2:c.1741C>T NP_001264984.1:p.Arg581Ter nonsense NC_000013.11:g.23353788G>A NC_000013.10:g.23927927G>A NG_012342.1:g.84915C>T - Protein change
- R728*, R581*
- Other names
- NM_014363.6(SACS):c.2182C>T
- p.Arg728Ter
- Canonical SPDI
- NC_000013.11:23353787:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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SACS | - | - |
GRCh38 GRCh37 |
3994 | 4188 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Likely pathogenic (1) |
criteria provided, single submitter
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- | RCV000454220.1 | |
Pathogenic (1) |
criteria provided, single submitter
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May 31, 2016 | RCV000393719.1 | |
Pathogenic/Likely pathogenic (9) |
criteria provided, multiple submitters, no conflicts
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Sep 12, 2023 | RCV000984212.14 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 28, 2023 | RCV001859535.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 12, 2016 | RCV001848046.3 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: research
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Abnormal brain morphology
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
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Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine
Accession: SCV000537976.1
First in ClinVar: Apr 03, 2017 Last updated: Apr 03, 2017 |
Geographic origin: Turkey
Tissue: Blood
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Pathogenic
(May 31, 2016)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000329912.6
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
The R728X variant in the SACS gene has been reported previously in the homozygous and compound heterozygous states in association with cerebellar ataxia (Vermeer et … (more)
The R728X variant in the SACS gene has been reported previously in the homozygous and compound heterozygous states in association with cerebellar ataxia (Vermeer et al., 2008; Synofzik et al., 2013; Karaca et al., 2015). This variant is predicted to cause loss of normal protein function through protein truncation. The R728X variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret R728X as a pathogenic variant. (less)
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Pathogenic
(Dec 01, 2020)
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criteria provided, single submitter
Method: clinical testing
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Charlevoix-Saguenay spastic ataxia
Affected status: yes
Allele origin:
germline
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CMT Laboratory, Bogazici University
Accession: SCV001548315.1
First in ClinVar: Apr 03, 2021 Last updated: Apr 03, 2021 |
Number of individuals with the variant: 1
Family history: yes
Secondary finding: no
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Pathogenic
(Sep 05, 2021)
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criteria provided, single submitter
Method: clinical testing
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Charlevoix-Saguenay spastic ataxia
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002027666.1
First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021 |
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Pathogenic
(Dec 12, 2016)
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criteria provided, single submitter
Method: clinical testing
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Hereditary spastic paraplegia
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002105012.1
First in ClinVar: Mar 19, 2022 Last updated: Mar 19, 2022 |
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Pathogenic
(Apr 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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Charlevoix-Saguenay spastic ataxia
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002511803.1
First in ClinVar: May 16, 2022 Last updated: May 16, 2022 |
Comment:
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 … (more)
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. (less)
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Likely pathogenic
(Jan 25, 2023)
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criteria provided, single submitter
Method: curation
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Charlevoix-Saguenay spastic ataxia
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV003761331.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
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 … (more)
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). (less)
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Pathogenic
(Sep 12, 2023)
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criteria provided, single submitter
Method: clinical testing
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Charlevoix-Saguenay spastic ataxia
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004209912.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(Mar 31, 2022)
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criteria provided, single submitter
Method: clinical testing
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Charlevoix-Saguenay spastic ataxia
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003814524.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Oct 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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Spastic paraplegia
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002141331.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024 |
Comment:
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, … (more)
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. (less)
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Likely pathogenic
(Jan 02, 2014)
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no assertion criteria provided
Method: clinical testing
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Charlevoix-Saguenay spastic ataxia
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV001132279.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
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Pathogenic
(Dec 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Charlevoix-Saguenay type spastic ataxia
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002086722.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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Pathogenic
(Oct 28, 2023)
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no assertion criteria provided
Method: research
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Charlevoix-Saguenay spastic ataxia
Affected status: yes
Allele origin:
germline
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Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology
Accession: SCV004812219.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Ethnicity/Population group: Pashtun
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Clinical, ophthalmological, imaging and genetic features in Brazilian patients with ARSACS. | Rezende Filho FM | Parkinsonism & related disorders | 2019 | PMID: 30638817 |
Autosomal-Recessive Spastic Ataxia of Charlevoix-Saguenay: A Turkish Child. | Incecik F | Journal of pediatric neurosciences | 2018 | PMID: 30271475 |
A reduction in Drp1-mediated fission compromises mitochondrial health in autosomal recessive spastic ataxia of Charlevoix Saguenay. | Bradshaw TY | Human molecular genetics | 2016 | PMID: 27288452 |
Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease. | Karaca E | Neuron | 2015 | PMID: 26539891 |
EFNS/ENS Consensus on the diagnosis and management of chronic ataxias in adulthood. | van de Warrenburg BP | European journal of neurology | 2014 | PMID: 24418350 |
Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS): expanding the genetic, clinical and imaging spectrum. | Synofzik M | Orphanet journal of rare diseases | 2013 | PMID: 23497566 |
ARSACS in the Dutch population: a frequent cause of early-onset cerebellar ataxia. | Vermeer S | Neurogenetics | 2008 | PMID: 18465152 |
Text-mined citations for rs752059006 ...
HelpRecord last updated Jun 02, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.