ClinVar Genomic variation as it relates to human health
NM_014946.4(SPAST):c.1245+5G>A
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.
Pathogenic(3); Uncertain significance(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.1245+5G>A
Variation ID: 546862 Accession: VCV000546862.35
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p22.3 2: 32128484 (GRCh38) [ NCBI UCSC ] 2: 32353553 (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 Jul 9, 2018 Oct 8, 2024 Apr 6, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_014946.4:c.1245+5G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001363823.2:c.1242+5G>A intron variant NM_001363875.2:c.1146+5G>A intron variant NM_001377959.1:c.1149+5G>A intron variant NM_199436.2:c.1149+5G>A intron variant NC_000002.12:g.32128484G>A NC_000002.11:g.32353553G>A NG_008730.1:g.69874G>A LRG_714:g.69874G>A LRG_714t1:c.1245+5G>A - Protein change
- Other names
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- Canonical SPDI
- NC_000002.12:32128483: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.
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- Links
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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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 (3) |
criteria provided, multiple submitters, no conflicts
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Apr 6, 2022 | RCV001729680.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 1, 2018 | RCV000658864.22 |
Submissions - Germline
Classification
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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
(Oct 01, 2021)
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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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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV001976987.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
Comment:
PM1, PM2, PP3, PP4, PP5
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Uncertain significance
(Feb 01, 2018)
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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: SCV000780661.28
First in ClinVar: Jul 09, 2018 Last updated: Oct 08, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Apr 06, 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: SCV002316669.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 546862). This sequence change falls in intron 9 of the SPAST gene. It does not directly … (more)
ClinVar contains an entry for this variant (Variation ID: 546862). This sequence change falls in intron 9 of the SPAST gene. It does not directly change the encoded amino acid sequence of the SPAST protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of hereditary spastic paraplegia (PMID: 22552817, 30476002, 33638609, 34008892; Invitae). It has also been observed to segregate with disease in related individuals. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 9, but is expected to preserve the integrity of the reading-frame (PMID: 33638609). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(May 25, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary spastic paraplegia 4
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557460.2
First in ClinVar: Aug 04, 2022 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms … (more)
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. Multiple premature termination codon variants resulting in loss of function have been reported whilst a missense variant has been shown to have gain of function effects (ClinVar; PMID 24478365; PMID 30520996). (N) 0104 - Dominant Negative is a mechanism of disease for this gene for other missense variants (PMID 30006150). (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0112 - Variants in this gene are known to have reduced penetrance (PMID 30476002). (N) 0212 - Non-canonical splice variant without proven consequence on splicing (no functional evidence available) (intron 9 of 16). (P) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (P) 0702 - Comparable variants have strong previous evidence for pathogenicity. Multiple non-canonical splice variants within the same donor region have previously been reported in clinical cases (ClinVar; PMID 22552817; PMID 24648003; PMID 11309678). (P) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times in association with hereditary spastic paraplegia (ClinVar; PMID 27260292; PMID 22552817; PMID 28572275). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign (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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Phenotype-driven variant filtration strategy in exome sequencing toward a high diagnostic yield and identification of 85 novel variants in 400 patients with rare Mendelian disorders. | Marinakis NM | American journal of medical genetics. Part A | 2021 | PMID: 34008892 |
The investigation of genetic and clinical features in patients with hereditary spastic paraplegia in central-Southern China. | Wang C | Molecular genetics & genomic medicine | 2021 | PMID: 33638609 |
Hereditary spastic paraplegia: gain-of-function mechanisms revealed by new transgenic mouse. | Qiang L | Human molecular genetics | 2019 | PMID: 30520996 |
Spastic paraplegia due to SPAST mutations is modified by the underlying mutation and sex. | Parodi L | Brain : a journal of neurology | 2018 | PMID: 30476002 |
Missense mutation of SPAST protein (I344K) results in loss of ATPase activity and prolonged the half-life, implicated in autosomal dominant hereditary spastic paraplegia. | Lim JH | Biochimica et biophysica acta. Molecular basis of disease | 2018 | PMID: 30006150 |
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 |
A series of Greek children with pure hereditary spastic paraplegia: clinical features and genetic findings. | Polymeris AA | Journal of neurology | 2016 | PMID: 27260292 |
Hand muscles corticomotor excitability in hereditary spastic paraparesis type 4. | Ginanneschi F | Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology | 2014 | PMID: 24648003 |
Pathogenic mutation of spastin has gain-of-function effects on microtubule dynamics. | Solowska JM | The Journal of neuroscience : the official journal of the Society for Neuroscience | 2014 | PMID: 24478365 |
A high-throughput resequencing microarray for autosomal dominant spastic paraplegia genes. | Dufke C | Neurogenetics | 2012 | PMID: 22552817 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Identification and expression analysis of spastin gene mutations in hereditary spastic paraplegia. | Svenson IK | American journal of human genetics | 2001 | PMID: 11309678 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
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Text-mined citations for rs1553317049 ...
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.