Different missense changes at this residue (R562G, R562P) has been reported in the published literature (Svenson et al., 2004; de Bot et al., 2010); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 29934652, 24451228, 22552817, 25326637, 11843700, 19423133)
ClinVar Genomic variation as it relates to human health
NM_014946.4(SPAST):c.1685G>A (p.Arg562Gln)
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.
(10)
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
10
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.1685G>A (p.Arg562Gln)
Variation ID: 217004 Accession: VCV000217004.43
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2p22.3 2: 32145005 (GRCh38) [ NCBI UCSC ] 2: 32370074 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 11, 2015 Nov 24, 2024 Nov 12, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_014946.4:c.1685G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_055761.2:p.Arg562Gln missense NM_001363823.2:c.1682G>A NP_001350752.1:p.Arg561Gln missense NM_001363875.2:c.1586G>A NP_001350804.1:p.Arg529Gln missense NM_001377959.1:c.1520+1590G>A intron variant NM_199436.2:c.1589G>A NP_955468.1:p.Arg530Gln missense NC_000002.12:g.32145005G>A NC_000002.11:g.32370074G>A NG_008730.1:g.86395G>A LRG_714:g.86395G>A LRG_714t1:c.1685G>A LRG_714p1:p.Arg562Gln Q9UBP0:p.Arg562Gln - Protein change
- R562Q, R530Q, R561Q, R529Q
- Other names
- -
- Canonical SPDI
- NC_000002.12:32145004:G:A
-
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.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
- 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 |
1335 | 1402 | |
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
|
Nov 12, 2024 | RCV000195806.12 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 1, 2024 | RCV001091364.26 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Jan 1, 2020 | RCV001847904.4 | |
|
SPAST-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
Sep 15, 2022 | RCV003401083.4 |
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
(Jun 24, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Spastic paraplegia 4, autosomal dominant
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
|
UCLA Clinical Genomics Center, UCLA
Study: CES
Accession: SCV000255473.2 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Age: 50-59 years
Sex: male
Testing laboratory: UCLA Clinical Genomics Center
|
|
|
Likely pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 4
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893608.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Likely pathogenic
(Sep 30, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001819097.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
Different missense changes at this residue (R562G, R562P) has been reported in the published literature (Svenson et al., 2004; de Bot et al., 2010); In … (more)
Different missense changes at this residue (R562G, R562P) has been reported in the published literature (Svenson et al., 2004; de Bot et al., 2010); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 29934652, 24451228, 22552817, 25326637, 11843700, 19423133) (less)
|
|
|
Likely pathogenic
(Jan 01, 2020)
|
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: SCV002105622.1
First in ClinVar: Mar 19, 2022 Last updated: Mar 19, 2022 |
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: not provided
|
Hereditary spastic paraplegia 4
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, University Hospital of Duesseldorf
Accession: SCV004046798.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
|
|
|
Pathogenic
(Sep 15, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
SPAST-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004120947.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The SPAST c.1685G>A variant is predicted to result in the amino acid substitution p.Arg562Gln. This variant (also known as G1810A, R562Q) was reported in multiple … (more)
The SPAST c.1685G>A variant is predicted to result in the amino acid substitution p.Arg562Gln. This variant (also known as G1810A, R562Q) was reported in multiple individual with autosomal dominant hereditary spastic paraplegia (Table 3, Meijer et al 2002. PubMed ID: 11843700; Supplemental Table e2, Lee et al 2014. PubMed ID: 25326637; Table 1, Orlacchio et al. 2008. PubMed ID: 17971434; Table 1, Svenstrup et al 2009. PubMed ID: 19423133). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. (less)
|
|
|
Pathogenic
(Dec 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 4
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001207900.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant disrupts the p.Arg562 amino acid residue in SPAST. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15248095; Invitae). … (more)
This variant disrupts the p.Arg562 amino acid residue in SPAST. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15248095; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). ClinVar contains an entry for this variant (Variation ID: 217004). This missense change has been observed in individuals with hereditary spastic paraplegia (PMID: 11843700, 17971434, 19423133, 25326637, 27334366). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 562 of the SPAST protein (p.Arg562Gln). (less)
|
|
|
Likely pathogenic
(Oct 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001247364.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(Nov 12, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 4
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV005395907.1
First in ClinVar: Nov 17, 2024 Last updated: Nov 17, 2024 |
Clinical Features:
Spastic paraplegia (present) , Impaired vibratory sensation (present) , Progressive spastic paraparesis (present)
|
|
|
Pathogenic
(Mar 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV005413247.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
PP3, PM1, PM2_moderate, PM5, PS4
Number of individuals with the variant: 2
|
Comment:
Comment:
The SPAST c.1685G>A variant is predicted to result in the amino acid substitution p.Arg562Gln. This variant (also known as G1810A, R562Q) was reported in multiple individual with autosomal dominant hereditary spastic paraplegia (Table 3, Meijer et al 2002. PubMed ID: 11843700; Supplemental Table e2, Lee et al 2014. PubMed ID: 25326637; Table 1, Orlacchio et al. 2008. PubMed ID: 17971434; Table 1, Svenstrup et al 2009. PubMed ID: 19423133). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
Comment:
This variant disrupts the p.Arg562 amino acid residue in SPAST. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15248095; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). ClinVar contains an entry for this variant (Variation ID: 217004). This missense change has been observed in individuals with hereditary spastic paraplegia (PMID: 11843700, 17971434, 19423133, 25326637, 27334366). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 562 of the SPAST protein (p.Arg562Gln).
Comment:
PP3, PM1, PM2_moderate, PM5, PS4
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:
Different missense changes at this residue (R562G, R562P) has been reported in the published literature (Svenson et al., 2004; de Bot et al., 2010); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 29934652, 24451228, 22552817, 25326637, 11843700, 19423133)
Comment:
The SPAST c.1685G>A variant is predicted to result in the amino acid substitution p.Arg562Gln. This variant (also known as G1810A, R562Q) was reported in multiple individual with autosomal dominant hereditary spastic paraplegia (Table 3, Meijer et al 2002. PubMed ID: 11843700; Supplemental Table e2, Lee et al 2014. PubMed ID: 25326637; Table 1, Orlacchio et al. 2008. PubMed ID: 17971434; Table 1, Svenstrup et al 2009. PubMed ID: 19423133). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
Comment:
This variant disrupts the p.Arg562 amino acid residue in SPAST. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15248095; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). ClinVar contains an entry for this variant (Variation ID: 217004). This missense change has been observed in individuals with hereditary spastic paraplegia (PMID: 11843700, 17971434, 19423133, 25326637, 27334366). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 562 of the SPAST protein (p.Arg562Gln).
Comment:
PP3, PM1, PM2_moderate, PM5, PS4
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genetic, structural and clinical analysis of spastic paraplegia 4. | Varghaei P | Parkinsonism & related disorders | 2022 | PMID: 35487127 |
| Spastic paraplegia due to SPAST mutations is modified by the underlying mutation and sex. | Parodi L | Brain : a journal of neurology | 2018 | PMID: 30476002 |
| SPAST mutation spectrum and familial occurrence among Czech patients with pure hereditary spastic paraplegia. | Mészárosová AU | Journal of human genetics | 2016 | PMID: 27334366 |
| Clinical exome sequencing for genetic identification of rare Mendelian disorders. | Lee H | JAMA | 2014 | PMID: 25326637 |
| Sequence variants in SPAST, SPG3A and HSPD1 in hereditary spastic paraplegia. | Svenstrup K | Journal of the neurological sciences | 2009 | PMID: 19423133 |
| Spastic paraplegia in Romania: high prevalence of SPG4 mutations. | Orlacchio A | Journal of neurology, neurosurgery, and psychiatry | 2008 | PMID: 17971434 |
| Intragenic modifiers of hereditary spastic paraplegia due to spastin gene mutations. | Svenson IK | Neurogenetics | 2004 | PMID: 15248095 |
| Spectrum of SPG4 mutations in a large collection of North American families with hereditary spastic paraplegia. | Meijer IA | Archives of neurology | 2002 | PMID: 11843700 |
Text-mined citations for rs863224923 ...
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 Nov 25, 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.