ClinVar Genomic variation as it relates to human health
NM_014946.4(SPAST):c.1735A>C (p.Asn579His)
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(7); Benign(1); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_014946.4(SPAST):c.1735A>C (p.Asn579His)
Variation ID: 212290 Accession: VCV000212290.53
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p22.3 2: 32154380 (GRCh38) [ NCBI UCSC ] 2: 32379449 (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 Oct 5, 2015 Sep 16, 2024 Jan 18, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_014946.4:c.1735A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_055761.2:p.Asn579His missense NM_001363823.2:c.1732A>C NP_001350752.1:p.Asn578His missense NM_001363875.2:c.1636A>C NP_001350804.1:p.Asn546His missense NM_001377959.1:c.*8A>C 3 prime UTR NM_199436.2:c.1639A>C NP_955468.1:p.Asn547His missense NC_000002.12:g.32154380A>C NC_000002.11:g.32379449A>C NG_008730.1:g.95770A>C LRG_714:g.95770A>C LRG_714t1:c.1735A>C LRG_714p1:p.Asn579His Q9UBP0:p.Asn579His - Protein change
- N579H, N547H, N546H, N578H
- Other names
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- Canonical SPDI
- NC_000002.12:32154379: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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0.00020 (C)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Trans-Omics for Precision Medicine (TOPMed) 0.00029
The Genome Aggregation Database (gnomAD) 0.00031
The Genome Aggregation Database (gnomAD), exomes 0.00038
Exome Aggregation Consortium (ExAC) 0.00046
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00069
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
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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SPAST | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1316 | 1383 |
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
Help
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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Aug 3, 2023 | RCV000193599.10 | |
Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Jan 18, 2024 | RCV000509114.19 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Dec 21, 2023 | RCV000658865.28 | |
Uncertain significance (1) |
criteria provided, single submitter
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- | RCV001391562.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 4, 2021 | RCV001640291.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 28, 2019 | RCV001847874.5 |
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
(Jun 27, 2014)
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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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Genetic Services Laboratory, University of Chicago
Accession: SCV000249012.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
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Likely benign
(Jan 18, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary spastic paraplegia 4
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000645354.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
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Uncertain significance
(Dec 01, 2021)
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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: SCV000780662.27
First in ClinVar: Jul 09, 2018 Last updated: Aug 04, 2024 |
Number of individuals with the variant: 3
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Uncertain significance
(Dec 21, 2023)
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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: SCV000565590.6
First in ClinVar: Oct 05, 2015 Last updated: Sep 16, 2024 |
Comment:
Reported in an individual with an apparently sporadic, adult-onset upper motor neuron syndrome (PMID: 16240363); Reported in two individuals with hereditary spastic paraplegia who harbored … (more)
Reported in an individual with an apparently sporadic, adult-onset upper motor neuron syndrome (PMID: 16240363); Reported in two individuals with hereditary spastic paraplegia who harbored a second SPAST variant; however, phase is unknown as parental testing was not performed (PMID: 16055926, 28572275); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20562464, 17594340, 30476002, 24451228, 28572275, 16055926, 34426522, 34445196, 21139634, 26094131, 16240363, 34983064, 27535533) (less)
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Benign
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hereditary spastic paraplegia 4
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001301641.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. (less)
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Uncertain significance
(-)
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criteria provided, single submitter
Method: clinical testing
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Spastic paraplegia
Affected status: yes
Allele origin:
unknown
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Paris Brain Institute, Inserm - ICM
Accession: SCV001451333.1
First in ClinVar: May 16, 2021 Last updated: May 16, 2021 |
Number of individuals with the variant: 1
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Uncertain significance
(Jan 04, 2021)
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criteria provided, single submitter
Method: research
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Spastic ataxia
Affected status: yes
Allele origin:
unknown
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Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris
Accession: SCV001519251.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
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Uncertain significance
(Jan 28, 2019)
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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: SCV002105624.1
First in ClinVar: Mar 19, 2022 Last updated: Mar 19, 2022 |
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Uncertain significance
(Aug 03, 2023)
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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: SCV004039461.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
Comment:
Variant summary: SPAST c.1735A>C (p.Asn579His) results in a conservative amino acid change located in the Spastin/Vps4, C-terminal (IPR015415) of the encoded protein sequence. Three of … (more)
Variant summary: SPAST c.1735A>C (p.Asn579His) results in a conservative amino acid change located in the Spastin/Vps4, C-terminal (IPR015415) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00038 in 250738 control chromosomes, predominantly at a frequency of 0.00072 within the Non-Finnish European subpopulation in the gnomAD database. c.1735A>C has been reported in the literature in individuals affected with Spastic Paraplegia or hereditary ataxia without strong evidence of causality (Brugman_2005, Depienne_2006, Chelban_2017, Parodi_2018, Gelatolo_2021). These reports do not provide unequivocal conclusions about association of the variant with Spastic Paraplegia 4, Autosomal Dominant. Co-occurrence with another pathogenic/likely pathogenic variant has been reported (SPAST c.1216A>G, p.Ile406Val, Depienne_2006), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 16240363, 16055926, 28572275, 30476002, 34445196). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=4), benign (n=1) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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not provided
(-)
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no classification provided
Method: phenotyping only
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Not Provided
Affected status: unknown
Allele origin:
maternal
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GenomeConnect, ClinGen
Accession: SCV000986750.1
First in ClinVar: Aug 31, 2019 Last updated: Aug 31, 2019 |
Comment:
Variant interpretted as not providedand reported on 04/10/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from … (more)
Variant interpretted as not providedand reported on 04/10/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Abnormality of the amniotic fluid (present) , Decreased fetal movement (present) , Abnormal delivery (present) , Prenatal maternal abnormality (present) , Abnormality of the placenta … (more)
Abnormality of the amniotic fluid (present) , Decreased fetal movement (present) , Abnormal delivery (present) , Prenatal maternal abnormality (present) , Abnormality of the placenta (present) , Abnormality of the umbilical cord (present) , Premature birth (present) , Generalized hypotonia (present) , Multiple cafe-au-lait spots (present) , Abnormality of facial musculature (present) , Abnormality of muscle physiology (present) , Abnormality of the musculature of the limbs (present) , Feeding difficulties (present) (less)
Age: 0-9 years
Sex: female
Testing laboratory: GeneDx
Date variant was reported to submitter: 2018-04-10
Testing laboratory interpretation: not provided
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not provided
(-)
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Flagged submission
flagged submission
Method: phenotyping only
Reason: This record appears to be redundant with a more recent record from the same submitter.
Notes: SCV000607201 appears to be redundant with SCV000986750.
(less)
Notes: SCV000607201 appears to
(...more)
Source: NCBI
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Hereditary spastic paraplegia 4
Affected status: unknown
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV000607201.1
First in ClinVar: Oct 16, 2017 Last updated: Oct 16, 2017 |
Comment:
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical … (more)
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Myopia (present) , Generalized hypotonia (present) , Hypertonia (present) , Abnormality of coordination (present) , Abnormality of the musculature of the limbs (present) , Abnormality … (more)
Myopia (present) , Generalized hypotonia (present) , Hypertonia (present) , Abnormality of coordination (present) , Abnormality of the musculature of the limbs (present) , Abnormality of muscle physiology (present) , Abnormality of the bladder (present) (less)
Indication for testing: Diagnostic
Age: 40-49 years
Sex: female
Testing laboratory: GeneDx
Date variant was reported to submitter: 2016-12-23
Testing laboratory interpretation: Uncertain significance
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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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NGS in Hereditary Ataxia: When Rare Becomes Frequent. | Galatolo D | International journal of molecular sciences | 2021 | PMID: 34445196 |
Spastic paraplegia due to SPAST mutations is modified by the underlying mutation and sex. | Parodi L | Brain : a journal of neurology | 2018 | PMID: 30476002 |
Truncating mutations in SPAST patients are associated with a high rate of psychiatric comorbidities in hereditary spastic paraplegia. | Chelban V | Journal of neurology, neurosurgery, and psychiatry | 2017 | PMID: 28572275 |
Spastin mutations are frequent in sporadic spastic paraparesis and their spectrum is different from that observed in familial cases. | Depienne C | Journal of medical genetics | 2006 | PMID: 16055926 |
Spastin mutations in sporadic adult-onset upper motor neuron syndromes. | Brugman F | Annals of neurology | 2005 | PMID: 16240363 |
Text-mined citations for rs144594804 ...
HelpRecord last updated Sep 17, 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.