ClinVar Genomic variation as it relates to human health
NM_014946.4(SPAST):c.1276C>T (p.Leu426Phe)
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.1276C>T (p.Leu426Phe)
Variation ID: 448444 Accession: VCV000448444.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p22.3 2: 32136593 (GRCh38) [ NCBI UCSC ] 2: 32361662 (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 19, 2017 Jun 9, 2024 Nov 30, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_014946.4:c.1276C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_055761.2:p.Leu426Phe missense NM_001363823.2:c.1273C>T NP_001350752.1:p.Leu425Phe missense NM_001363875.2:c.1177C>T NP_001350804.1:p.Leu393Phe missense NM_001377959.1:c.1180C>T NP_001364888.1:p.Leu394Phe missense NM_199436.2:c.1180C>T NP_955468.1:p.Leu394Phe missense NC_000002.12:g.32136593C>T NC_000002.11:g.32361662C>T NG_008730.1:g.77983C>T LRG_714:g.77983C>T LRG_714t1:c.1276C>T LRG_714p1:p.Leu426Phe - Protein change
- L426F, L393F, L394F, L425F
- Other names
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- Canonical SPDI
- NC_000002.12:32136592:C:T
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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 |
1316 | 1383 |
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 (1) |
criteria provided, single submitter
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Jan 1, 2017 | RCV000626922.2 | |
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Nov 30, 2023 | RCV000644897.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 30, 2021 | RCV003482273.2 |
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
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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 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Flexion contracture
Spastic diplegia Spasticity Pes valgus Tip-toe gait
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000747625.1
First in ClinVar: May 12, 2018 Last updated: May 12, 2018 |
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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: SCV001450970.1
First in ClinVar: May 16, 2021 Last updated: May 16, 2021 |
Number of individuals with the variant: 2
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Likely pathogenic
(Mar 25, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary spastic paraplegia 4
Affected status: yes
Allele origin:
germline
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DASA
Accession: SCV002318969.1
First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022 |
Comment:
The c.1276C>T;p.(Leu426Phe) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 448444; PMID: 20214791)-PS4_moderate. The variant … (more)
The c.1276C>T;p.(Leu426Phe) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 448444; PMID: 20214791)-PS4_moderate. The variant is located in a mutational hot spot and/or critical and well-established functional domain (RuvB_N; AAA) - PM1. This variant is not present in population databases (rs1060502227- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br.) - PM2. Pathogenic missense variant in this residue have been reported (ClinVar ID: 409031) - PM5. The variant co-segregated with disease in multiple affected family members (PMID: 20214791)PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is likely pathogenic (less)
Number of individuals with the variant: 1
Sex: male
Geographic origin: Brazil
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Pathogenic
(Sep 30, 2021)
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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: SCV000615385.2
First in ClinVar: Dec 19, 2017 Last updated: Jan 26, 2024 |
Comment:
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). At least one other missense variant at this codon is considered to be … (more)
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. This variant has been confirmed to occur de novo in one individual with clinical features associated with this gene. Computational tools predict that this variant is damaging. (less)
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Pathogenic
(Jul 22, 2023)
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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: SCV000766615.4
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the … (more)
This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu426 amino acid residue in SPAST. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10699187, 11809724, 11843700, 15841487, 20718791, 20932283, 22960362). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 448444). This missense change has been observed in individual(s) with hereditary spastic paraplegia (PMID: 20214791, 29761117, 29934652; Invitae). 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. This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 426 of the SPAST protein (p.Leu426Phe). (less)
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Pathogenic
(Nov 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary spastic paraplegia 4
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004183472.2
First in ClinVar: Dec 24, 2023 Last updated: Jun 09, 2024 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Hereditary spastic paraplegia 4
Affected status: yes
Allele origin:
unknown
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GenomeConnect - Brain Gene Registry
Accession: SCV003931146.1
First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023 |
Comment:
Variant classified as Pathogenic and reported on 11-13-2020 by GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does … (more)
Variant classified as Pathogenic and reported on 11-13-2020 by GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. (less)
Clinical Features:
Tip-toe gait (present) , Lower limb spasticity (present)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: male
Method: Gene Panel Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2020-11-13
Testing laboratory interpretation: Pathogenic
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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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Targeted next-generation sequencing improves diagnosis of hereditary spastic paraplegia in Chinese patients. | Lu C | Journal of molecular medicine (Berlin, Germany) | 2018 | PMID: 29934652 |
Genomic analysis identifies masqueraders of full-term cerebral palsy. | Takezawa Y | Annals of clinical and translational neurology | 2018 | PMID: 29761117 |
Novel and recurrent spastin mutations in a large series of SPG4 Italian families. | Nanetti L | Neuroscience letters | 2012 | PMID: 22960362 |
Mutation screening of spastin, atlastin, and REEP1 in hereditary spastic paraplegia. | McCorquodale DS 3rd | Clinical genetics | 2011 | PMID: 20718791 |
Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in Spanish patients with hereditary spastic paraplegia. | Alvarez V | BMC neurology | 2010 | PMID: 20932283 |
Unique spectrum of SPAST variants in Estonian HSP patients: presence of benign missense changes but lack of exonic rearrangements. | Braschinsky M | BMC neurology | 2010 | PMID: 20214791 |
Autosomal dominant hereditary spastic paraplegia: DHPLC-based mutation analysis of SPG4 reveals eleven novel mutations. | Patrono C | Human mutation | 2005 | PMID: 15841487 |
Spectrum of SPG4 mutations in a large collection of North American families with hereditary spastic paraplegia. | Meijer IA | Archives of neurology | 2002 | PMID: 11843700 |
Spastin, the protein mutated in autosomal dominant hereditary spastic paraplegia, is involved in microtubule dynamics. | Errico A | Human molecular genetics | 2002 | PMID: 11809724 |
Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia. | Fonknechten N | Human molecular genetics | 2000 | PMID: 10699187 |
Text-mined citations for rs1060502227 ...
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.