The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Computational tools predict that this variant is damaging.
ClinVar Genomic variation as it relates to human health
NM_014946.4(SPAST):c.1507C>T (p.Arg503Trp)
Germline
Classification
Help
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.
(8)
Help
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/Likely pathogenic
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_014946.4(SPAST):c.1507C>T (p.Arg503Trp)
Variation ID: 219575 Accession: VCV000219575.68
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p22.3 2: 32141917 (GRCh38) [ NCBI UCSC ] 2: 32366986 (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 Mar 3, 2018 Oct 20, 2024 Apr 27, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_014946.4:c.1507C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_055761.2:p.Arg503Trp missense NM_001363823.2:c.1504C>T NP_001350752.1:p.Arg502Trp missense NM_001363875.2:c.1408C>T NP_001350804.1:p.Arg470Trp missense NM_001377959.1:c.1411C>T NP_001364888.1:p.Arg471Trp missense NM_199436.2:c.1411C>T NP_955468.1:p.Arg471Trp missense NC_000002.12:g.32141917C>T NC_000002.11:g.32366986C>T NG_008730.1:g.83307C>T LRG_714:g.83307C>T LRG_714t1:c.1507C>T LRG_714p1:p.Arg503Trp Q9UBP0:p.Arg503Trp - Protein change
- R503W, R470W, R471W, R502W
- Other names
- -
- Canonical SPDI
- NC_000002.12:32141916:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00000
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| SPAST | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1326 | 1393 | |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Apr 27, 2023 | RCV000204046.22 | |
| Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 17, 2022 | RCV000585136.30 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 12, 2016 | RCV001847923.10 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Dec 12, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002105614.1
First in ClinVar: Mar 19, 2022 Last updated: Mar 19, 2022 |
|
|
|
Likely pathogenic
(Jan 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 4
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002579740.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS4_MOD, PM1, PM5, PM2_SUP, PP3
|
Number of individuals with the variant: 1
Sex: male
|
|
|
Likely pathogenic
(Mar 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV002771042.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical … (more)
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Computational tools predict that this variant is damaging. (less)
|
|
|
Likely pathogenic
(Apr 27, 2023)
|
criteria provided, single submitter
Method: research
|
Hereditary spastic paraplegia 4
Affected status: yes
Allele origin:
germline
|
Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)
Accession: SCV003920821.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
|
|
|
Pathogenic
(Oct 31, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 4
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000259516.9
First in ClinVar: Feb 02, 2016 Last updated: Feb 28, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 219575). This missense change has been observed in individuals with hereditary spastic paraplegia (PMID: 16055926, 17594340, … (more)
ClinVar contains an entry for this variant (Variation ID: 219575). This missense change has been observed in individuals with hereditary spastic paraplegia (PMID: 16055926, 17594340, 18701882, 20932283). This variant is present in population databases (no rsID available, gnomAD 0.005%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 503 of the SPAST protein (p.Arg503Trp). 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. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg503 amino acid residue in SPAST. Other variant(s) that disrupt this residue have been observed in individuals with SPAST-related conditions (PMID: 12552568, 26374131), which suggests that this may be a clinically significant amino acid residue. (less)
|
|
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Pathogenic
(Feb 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 4
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV003842143.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). The variant is located in a mutational … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.92; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000219575). Different missense changes at the same codon (p.Arg503Leu, p.Arg503Pro) have been reported to be associated with SPAST related disorder (PMID: 12552568, 26374131). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Seizure (present) , Spastic tetraplegia (present) , Global developmental delay (present) , Brain atrophy (present) , Secondary microcephaly (present)
|
|
|
Likely pathogenic
(Oct 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV000692984.30
First in ClinVar: Mar 03, 2018 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Feb 28, 2019)
|
no assertion criteria provided
Method: provider interpretation
|
Spastic paraplegia 4, autosomal dominant
Affected status: yes
Allele origin:
germline
|
Codex Genetics Limited
Accession: SCV000996004.1
First in ClinVar: Jan 06, 2020 Last updated: Jan 06, 2020 |
Age: 40-49 years
Sex: female
|
Comment:
Comment:
ClinVar contains an entry for this variant (Variation ID: 219575). This missense change has been observed in individuals with hereditary spastic paraplegia (PMID: 16055926, 17594340, 18701882, 20932283). This variant is present in population databases (no rsID available, gnomAD 0.005%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 503 of the SPAST protein (p.Arg503Trp). 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. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg503 amino acid residue in SPAST. Other variant(s) that disrupt this residue have been observed in individuals with SPAST-related conditions (PMID: 12552568, 26374131), which suggests that this may be a clinically significant amino acid residue.
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.92; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000219575). Different missense changes at the same codon (p.Arg503Leu, p.Arg503Pro) have been reported to be associated with SPAST related disorder (PMID: 12552568, 26374131). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
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. |
Comment:
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Computational tools predict that this variant is damaging.
Comment:
ClinVar contains an entry for this variant (Variation ID: 219575). This missense change has been observed in individuals with hereditary spastic paraplegia (PMID: 16055926, 17594340, 18701882, 20932283). This variant is present in population databases (no rsID available, gnomAD 0.005%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 503 of the SPAST protein (p.Arg503Trp). 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. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg503 amino acid residue in SPAST. Other variant(s) that disrupt this residue have been observed in individuals with SPAST-related conditions (PMID: 12552568, 26374131), which suggests that this may be a clinically significant amino acid residue.
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.92; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000219575). Different missense changes at the same codon (p.Arg503Leu, p.Arg503Pro) have been reported to be associated with SPAST related disorder (PMID: 12552568, 26374131). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| The Value of Parental Testing by Next-Generation Sequencing Includes the Detection of Germline Mosaicism. | Brewer CJ | The Journal of molecular diagnostics : JMD | 2020 | PMID: 32092540 |
| Spastic paraplegia due to SPAST mutations is modified by the underlying mutation and sex. | Parodi L | Brain : a journal of neurology | 2018 | PMID: 30476002 |
| Hereditary spastic paraplegia in Greece: characterisation of a previously unexplored population using next-generation sequencing. | Lynch DS | European journal of human genetics : EJHG | 2016 | PMID: 26374131 |
| Molecular epidemiology and clinical spectrum of hereditary spastic paraplegia in the Japanese population based on comprehensive mutational analyses. | Ishiura H | Journal of human genetics | 2014 | PMID: 24451228 |
| Novel and recurrent spastin mutations in a large series of SPG4 Italian families. | Nanetti L | Neuroscience letters | 2012 | PMID: 22960362 |
| Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in Spanish patients with hereditary spastic paraplegia. | Alvarez V | BMC neurology | 2010 | PMID: 20932283 |
| 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 |
| Seven novel mutations and four exon deletions in a collection of Norwegian patients with SPG4 hereditary spastic paraplegia. | Erichsen AK | European journal of neurology | 2007 | PMID: 17594340 |
| Eight novel mutations in SPG4 in a large sample of patients with hereditary spastic paraplegia. | Crippa F | Archives of neurology | 2006 | PMID: 16682546 |
| 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 |
| Screening of patients with hereditary spastic paraplegia reveals seven novel mutations in the SPG4 (Spastin) gene. | Proukakis C | Human mutation | 2003 | PMID: 12552568 |
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Text-mined citations for rs864622162 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 20, 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.