ClinVar Genomic variation as it relates to human health
NM_014946.4(SPAST):c.1216A>G (p.Ile406Val)
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_014946.4(SPAST):c.1216A>G (p.Ile406Val)
Variation ID: 5675 Accession: VCV000005675.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p22.3 2: 32128450 (GRCh38) [ NCBI UCSC ] 2: 32353519 (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 Apr 4, 2013 Sep 29, 2024 Jan 30, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_014946.4:c.1216A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_055761.2:p.Ile406Val missense NM_001363823.2:c.1213A>G NP_001350752.1:p.Ile405Val missense NM_001363875.2:c.1117A>G NP_001350804.1:p.Ile373Val missense NM_001377959.1:c.1120A>G NP_001364888.1:p.Ile374Val missense NM_199436.2:c.1120A>G NP_955468.1:p.Ile374Val missense NC_000002.12:g.32128450A>G NC_000002.11:g.32353519A>G NG_008730.1:g.69840A>G LRG_714:g.69840A>G LRG_714t1:c.1216A>G LRG_714p1:p.Ile406Val Q9UBP0:p.Ile406Val - Protein change
- I406V, I374V, I405V, I373V
- Other names
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- Canonical SPDI
- NC_000002.12:32128449:A:G
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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.
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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
Help
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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SPAST | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1323 | 1390 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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 (4) |
criteria provided, multiple submitters, no conflicts
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Jul 19, 2022 | RCV000006029.14 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 30, 2024 | RCV000497406.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 15, 2017 | RCV001847589.3 |
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
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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
(Jan 30, 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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GeneDx
Accession: SCV000589637.4
First in ClinVar: Aug 20, 2017 Last updated: Sep 29, 2024 |
Comment:
Identified in patients with HSP in published literature, but segregation data is limited or absent for these individuals due to the lack of clinical information … (more)
Identified in patients with HSP in published literature, but segregation data is limited or absent for these individuals due to the lack of clinical information provided and/or insufficient participation by informative family members (PMID: 16682546, 19423133, 20562464); Published functional studies demonstrate damaging effects, including aberrant in-frame splicing, destabilization of mutated transcript, and deficient in microtubule-severing activity (PMID: 16476945); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 30476002, 16832076, 20562464, 19423133, 16476945, 31157359, 16055926, 34758253, 21139634, 26094131, 31594988, 34983064, 16682546) (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Hereditary spastic paraplegia 4
Affected status: yes
Allele origin:
unknown
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Paris Brain Institute, Inserm - ICM
Accession: SCV001450959.1
First in ClinVar: May 16, 2021 Last updated: May 16, 2021 |
Number of individuals with the variant: 2
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Pathogenic
(Dec 16, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV001880483.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
Comment:
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant appears to occur de novo in one individual with clinical features … (more)
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant appears to occur de novo in one individual with clinical features associated with this gene. Computational tools yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive. This variant resulted in a 30-bp deletion when expressed in a cell line. However, only 20% of transcript was affected and it is unclear if this is sufficient aberrant transcript to cause disease (PMID 16476945). Computational tools predict that this variant is damaging. The variant is located in a region that is considered important for protein function and/or structure. (less)
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Pathogenic
(Aug 15, 2017)
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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: SCV002105588.1
First in ClinVar: Mar 19, 2022 Last updated: Mar 19, 2022 |
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Pathogenic
(Jul 19, 2022)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001388127.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 28, 2024 |
Comment:
This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is … (more)
This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 406 of the SPAST protein (p.Ile406Val). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SPAST protein function. ClinVar contains an entry for this variant (Variation ID: 5675). This missense change has been observed in individual(s) with hereditary spastic paraplegia and was observed to be de novo in at least one individual (PMID: 16476945, 16682546, 16832076, 17971434, 18701882, 19423133). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. (less)
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Pathogenic
(Feb 14, 2006)
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no assertion criteria provided
Method: literature only
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SPASTIC PARAPLEGIA 4
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000026211.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 11, 2019 |
Comment on evidence:
In a woman with spastic paraplegia (SPG4; 182601), Schickel et al. (2006) identified a heterozygous 1216A-G transition in exon 9 of the SPAST gene. Although … (more)
In a woman with spastic paraplegia (SPG4; 182601), Schickel et al. (2006) identified a heterozygous 1216A-G transition in exon 9 of the SPAST gene. Although the mutation was predicted to result in an ile406-to-val (I406V) substitution, RT-PCR and direct sequencing of lymphocyte-derived cDNA revealed a 30-bp in-frame deletion of nucleotides 1216 to 1245 in exon 9, corresponding to deletion of codons 406 to 415. Thus, the 1216A-G transition created a fully dominant ectopic splice donor site. Transfection experiments in human cells showed that the mutant spastin protein with the deletion showed normal subcellular localization but lacked microtubule-severing activity, consistent with haploinsufficiency. A mutant construct containing the I406V substitution showed subcellular localization and microtubule-severing activity that was similar to wildtype spastin protein, suggesting that the predicted amino acid substitution was not pathogenic. (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Hereditary spastic paraplegia 4
Affected status: yes
Allele origin:
germline
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Genomics England Pilot Project, Genomics England
Accession: SCV001760086.1
First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021 |
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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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De novo SPAST mutations may cause a complex SPG4 phenotype. | Schieving JH | Brain : a journal of neurology | 2019 | PMID: 31157359 |
Spastic paraplegia due to SPAST mutations is modified by the underlying mutation and sex. | Parodi L | Brain : a journal of neurology | 2018 | PMID: 30476002 |
Sequence variants in SPAST, SPG3A and HSPD1 in hereditary spastic paraplegia. | Svenstrup K | Journal of the neurological sciences | 2009 | PMID: 19423133 |
Expansion of mutation spectrum, determination of mutation cluster regions and predictive structural classification of SPAST mutations in hereditary spastic paraplegia. | Shoukier M | European journal of human genetics : EJHG | 2009 | PMID: 18701882 |
Spastic paraplegia in Romania: high prevalence of SPG4 mutations. | Orlacchio A | Journal of neurology, neurosurgery, and psychiatry | 2008 | PMID: 17971434 |
Clinical features of hereditary spastic paraplegia due to spastin mutation. | McDermott CJ | Neurology | 2006 | PMID: 16832076 |
Eight novel mutations in SPG4 in a large sample of patients with hereditary spastic paraplegia. | Crippa F | Archives of neurology | 2006 | PMID: 16682546 |
Unexpected pathogenic mechanism of a novel mutation in the coding sequence of SPG4 (spastin). | Schickel J | Neurology | 2006 | PMID: 16476945 |
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 |
Text-mined citations for rs587777757 ...
HelpRecord last updated Oct 08, 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.