ClinVar Genomic variation as it relates to human health
NM_014363.6(SACS):c.1373C>T (p.Thr458Ile)
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.
Uncertain significance(5); Benign(3); Likely benign(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_014363.6(SACS):c.1373C>T (p.Thr458Ile)
Variation ID: 282385 Accession: VCV000282385.55
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q12.12 13: 23355239 (GRCh38) [ NCBI UCSC ] 13: 23929378 (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 Oct 8, 2024 Aug 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_014363.6:c.1373C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_055178.3:p.Thr458Ile missense NM_001278055.2:c.932C>T NP_001264984.1:p.Thr311Ile missense NC_000013.11:g.23355239G>A NC_000013.10:g.23929378G>A NG_012342.1:g.83464C>T - Protein change
- T458I, T311I
- Other names
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- Canonical SPDI
- NC_000013.11:23355238: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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0.00080 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00062
1000 Genomes Project 0.00080
Trans-Omics for Precision Medicine (TOPMed) 0.00213
The Genome Aggregation Database (gnomAD) 0.00227
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00238
Exome Aggregation Consortium (ExAC) 0.00252
The Genome Aggregation Database (gnomAD), exomes 0.00264
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
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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
Help
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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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Dec 22, 2021 | RCV000516147.13 | |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Aug 1, 2024 | RCV000676372.44 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 31, 2024 | RCV001082461.14 | |
Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
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May 18, 2021 | RCV000603816.19 | |
Likely benign (1) |
criteria provided, single submitter
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Feb 25, 2022 | RCV001844110.9 | |
SACS-related disorder
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Uncertain significance (1) |
no assertion criteria provided
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Jan 5, 2024 | RCV003930065.2 |
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
Help
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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Uncertain significance
(Sep 21, 2015)
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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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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000744372.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
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Uncertain significance
(Aug 13, 2015)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000333837.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Benign
(Aug 01, 2024)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001148952.26
First in ClinVar: Feb 03, 2020 Last updated: Oct 08, 2024 |
Comment:
SACS: BS1, BS2
Number of individuals with the variant: 12
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Uncertain significance
(Mar 07, 2017)
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criteria provided, single submitter
Method: research
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Hereditary spastic paraplegia
Affected status: yes
Allele origin:
unknown
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Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde
Accession: SCV000574488.1
First in ClinVar: Dec 10, 2017 Last updated: Dec 10, 2017 |
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Likely benign
(May 18, 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: SCV001737270.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
Sex: mixed
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Benign
(Feb 06, 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: SCV000614939.3
First in ClinVar: Dec 06, 2016 Last updated: Jan 18, 2020 |
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Benign
(Feb 21, 2019)
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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: SCV000565514.3
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
This variant is associated with the following publications: (PMID: 23497566, 27433545, 23280630, 25401298)
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Likely benign
(Jan 31, 2024)
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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: SCV000562824.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 14, 2024 |
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Likely benign
(Feb 25, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002103868.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
Comment:
Variant summary: SACS c.1373C>T (p.Thr458Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: SACS c.1373C>T (p.Thr458Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0025 in 282826 control chromosomes, predominantly at a frequency of 0.022 within the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in SACS causing Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay phenotype (0.0079), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. c.1373C>T has been reported in the literature in individuals affected with Progressive myoclonus epilepsies, Hereditary ataxias and atypical Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay (Muona_2014, Nascimento_2016, Synofzik_2013, Vural_2021). These reports do not provide unequivocal conclusions about association of the variant with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=5), benign (n=2) and likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Uncertain significance
(Dec 22, 2021)
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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: SCV002104991.1
First in ClinVar: Mar 19, 2022 Last updated: Mar 19, 2022 |
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Uncertain significance
(Jan 23, 2018)
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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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Genomics England Pilot Project, Genomics England
Accession: SCV001760321.1
First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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Charlevoix-Saguenay spastic ataxia
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV000733512.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
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Uncertain significance
(Feb 19, 2016)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000802148.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Uncertain significance
(Jan 05, 2024)
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no assertion criteria provided
Method: clinical testing
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SACS-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004747013.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The SACS c.1373C>T variant is predicted to result in the amino acid substitution p.Thr458Ile. This variant was reported in multiple individuals with autosomal recessive hereditary … (more)
The SACS c.1373C>T variant is predicted to result in the amino acid substitution p.Thr458Ile. This variant was reported in multiple individuals with autosomal recessive hereditary spastic paraplegias (Romano et al 2013. PubMed ID: 23280630; Vural A et al 2021. PubMed ID: 33624863; Muona M et al 2014. PubMed ID: 25401298). This variant is reported in 2.2% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, which may be too common to be disease-causing. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Likely benign
(Jun 18, 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: SCV001464188.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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Charlevoix-Saguenay spastic ataxia
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001552907.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The p.Thr458Ile was identified in the proband in trans with the SACS p.Leu266Ile variant of uncertain significance. The p.Thr458Ile variant was previously identified in two … (more)
The p.Thr458Ile was identified in the proband in trans with the SACS p.Leu266Ile variant of uncertain significance. The p.Thr458Ile variant was previously identified in two patients with Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS), and classified as a VUS (Synofzik_2013_PMID:23497566). The variant was observed in homozygous state in a male patient with disease onset at age 30, who had gait disturbance, nystagmus, slight dysmetria, no dysarthria, no pyramidal damage, and urge incontinence. MRI revealed minor atrophy of the superior cerebellar vermis, an arachnoid cyst, and a thinning of the posterior mid-body of the corpus callosum. The p.Thr458Ile variant was also found in compound heterozygous  state (with p.Val995Phe) in a male patient with disease onset at age 20, whose symptoms comprised an early-onset triad of cerebellar ataxia, pyramidal tract signs (bilateral spasticity and extensorplantar response) and peripheral sensorimotor neuropathy. This patient had gait ataxia, cerebellar oculomotor disturbance, dysarthria, dysphagia, intention tremor, dysmetria, and spasiticity (Synofzik_2013_PMID:23497566). The variant was also observed in 14/3500 control chromosomes (heterozygous) (Synofzik_2013_PMID:23497566). The p.Thr458Ile variant was also observed in compound heterozygous state (with a 1.5 Mb macrodeletion), with teenage-onset disease, with severe cerebellar ataxia, mild spasticity, mild peripheral neuropathy, and abnormal fundoscopy (Romano_2012_PMID: 23280630). The p.Thr458Ile variant in compound heterozygous state (in trans with p.Pro2798Gln) in a female patient with multifocal myoclonus (onset 13 years old), tonic clonic seizures (onset 15 years old) as well as additional seizure types, cognitive decline, pyramidal signs, and cerebellar ataxia; the variant was considered likely pathogenic (Nascimento_2016_PMID:27433545). The p.Thr458Ile variant was found in compound heterozygous state (with p.Val995Phe) in a patient with moderate to severe gait ataxia, spasticity, and atrophy of cerebellar vermis with an age of onset before 20 years, and considered pathogenic (Kreuz_2010_Medizinische Genetik 1 Conference Abstracts 2010). The variant was identified in control databases in 720 of 282826 chromosomes (1 homozygous) at a frequency of 0.002546 (Genome Aggregation Database Feb 27, 2017). The variant was identified in dbSNP (rs61729954), ClinVar (Conflicting interpretations of pathogenicity. Uncertain significance [4], benign [2]. The variant was identified in the following populations: Ashkenazi Jewish in 233 of 10370 chromosomes (freq: 0.02247), Other in 32 of 7224 chromosomes (freq: 0.00443), European (non-Finnish) in 352 of 129148 chromosomes (freq: 0.002726), Latino in 55 of 35434 chromosomes (freq: 0.001552), South Asian in 23 of 30612 chromosomes (freq: 0.000751), European (Finnish) in 14 of 25116 chromosomes (freq: 0.000557), African in 11 of 24968 chromosomes (freq: 0.000441), but was not observed in East Asian populations. The p.Thr458 residue is conserved in mammals and other organisms. Computational analyses (SIFT, Polyphen2, MUT Assesor, DANN, MT, FATHMM, MetaLR, Revel) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogencity.  In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (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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The Complex Genetic Landscape of Hereditary Ataxias in Turkey and Implications in Clinical Practice. | Vural A | Movement disorders : official journal of the Movement Disorder Society | 2021 | PMID: 33624863 |
Massive sequencing of 70 genes reveals a myriad of missing genes or mechanisms to be uncovered in hereditary spastic paraplegias. | Morais S | European journal of human genetics : EJHG | 2017 | PMID: 28832565 |
Progressive myoclonus epilepsy associated with SACS gene mutations. | Nascimento FA | Neurology. Genetics | 2016 | PMID: 27433545 |
A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy. | Muona M | Nature genetics | 2015 | PMID: 25401298 |
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 |
Comparative analysis and functional mapping of SACS mutations reveal novel insights into sacsin repeated architecture. | Romano A | Human mutation | 2013 | PMID: 23280630 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SACS | - | - | - | - |
Text-mined citations for rs61729954 ...
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.