ClinVar Genomic variation as it relates to human health
NM_014363.6(SACS):c.10136T>G (p.Leu3379Ter)
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.10136T>G (p.Leu3379Ter)
Variation ID: 371410 Accession: VCV000371410.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q12.12 13: 23333740 (GRCh38) [ NCBI UCSC ] 13: 23907879 (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 Jan 6, 2017 Feb 14, 2024 Dec 4, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_014363.6:c.10136T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_055178.3:p.Leu3379Ter nonsense NM_001278055.2:c.9695T>G NP_001264984.1:p.Leu3232Ter nonsense NC_000013.11:g.23333740A>C NC_000013.10:g.23907879A>C NG_012342.1:g.104963T>G - Protein change
- L3379*, L3232*
- Other names
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- Canonical SPDI
- NC_000013.11:23333739:A:C
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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
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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 |
4056 | 4256 |
Conditions - Germline
Condition
Help
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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Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Aug 21, 2023 | RCV000412241.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 23, 2019 | RCV000992769.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 4, 2023 | RCV001861393.4 |
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
Help
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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Pathogenic
(Jul 23, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Athena Diagnostics
Accession: SCV001145303.1
First in ClinVar: Jan 19, 2020 Last updated: Jan 19, 2020 |
Comment:
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 … (more)
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. (less)
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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: SCV002027629.1
First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021 |
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Pathogenic
(Nov 07, 2022)
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criteria provided, single submitter
Method: clinical testing
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Charlevoix-Saguenay spastic ataxia
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Variantyx, Inc.
Accession: SCV002754536.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
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 … (more)
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. (less)
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Likely pathogenic
(Sep 19, 2016)
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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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Counsyl
Accession: SCV000486982.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Pathogenic
(Aug 18, 2021)
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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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Fulgent Genetics, Fulgent Genetics
Accession: SCV002805742.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely pathogenic
(Aug 21, 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: SCV004209928.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Dec 04, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002143921.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
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, … (more)
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. (less)
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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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Coordination and timing deficits in speech and swallowing in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). | Vogel AP | Journal of neurology | 2018 | PMID: 29968200 |
New practical definitions for the diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay. | Pilliod J | Annals of neurology | 2015 | PMID: 26288984 |
Sacs knockout mice present pathophysiological defects underlying autosomal recessive spastic ataxia of Charlevoix-Saguenay. | Larivière R | Human molecular genetics | 2015 | PMID: 25260547 |
Late-onset sacsinopathy diagnosed by exome sequencing and comparative genomic hybridization. | Pyle A | Journal of neurogenetics | 2013 | PMID: 24180463 |
Structural basis of defects in the sacsin HEPN domain responsible for autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). | Kozlov G | The Journal of biological chemistry | 2011 | PMID: 21507954 |
Molecular diagnosis of known recessive ataxias by homozygosity mapping with SNP arrays. | H'mida-Ben Brahim D | Journal of neurology | 2011 | PMID: 20798953 |
A novel mutation in the SACS gene associated with a complicated form of spastic ataxia. | Masciullo M | Journal of neurology | 2008 | PMID: 18604465 |
ARSACS in the Dutch population: a frequent cause of early-onset cerebellar ataxia. | Vermeer S | Neurogenetics | 2008 | PMID: 18465152 |
Text-mined citations for rs1057517250 ...
HelpRecord last updated Oct 13, 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.