This variant was identified as de novo (maternity and paternity confirmed).
ClinVar Genomic variation as it relates to human health
NM_014946.4(SPAST):c.1496G>A (p.Arg499His)
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.
(27)
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
27
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.1496G>A (p.Arg499His)
Variation ID: 240950 Accession: VCV000240950.57
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2p22.3 2: 32141906 (GRCh38) [ NCBI UCSC ] 2: 32366975 (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 Feb 8, 2018 Feb 14, 2024 Jan 13, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_014946.4:c.1496G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_055761.2:p.Arg499His missense NM_001363823.2:c.1493G>A NP_001350752.1:p.Arg498His missense NM_001363875.2:c.1397G>A NP_001350804.1:p.Arg466His missense NM_001377959.1:c.1400G>A NP_001364888.1:p.Arg467His missense NM_199436.2:c.1400G>A NP_955468.1:p.Arg467His missense NC_000002.12:g.32141906G>A NC_000002.11:g.32366975G>A NG_008730.1:g.83296G>A LRG_714:g.83296G>A LRG_714t1:c.1496G>A LRG_714p1:p.Arg499His Q9UBP0:p.Arg499His - Protein change
- R499H, R498H, R466H, R467H
- Other names
- -
- Canonical SPDI
- NC_000002.12:32141905: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.
- -
- 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 (17) |
criteria provided, multiple submitters, no conflicts
|
Jan 13, 2024 | RCV000230990.29 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Mar 17, 2016 | RCV000623007.2 | |
| Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Jul 28, 2022 | RCV000713467.21 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 16, 2020 | RCV001847990.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 10, 2021 | RCV001814125.1 | |
|
SPAST-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
Mar 10, 2023 | RCV003422150.4 |
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
(Jul 28, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 4
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Study: VKGL Data-share Consensus
Accession: SCV000743204.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018 |
|
|
|
Pathogenic
(Oct 14, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 4
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000745629.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018 |
|
|
|
Pathogenic
(Feb 21, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV000844078.1
First in ClinVar: Oct 20, 2018 Last updated: Oct 20, 2018 |
|
|
|
Pathogenic
(Aug 21, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 4
Affected status: yes
Allele origin:
germline
|
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals
Accession: SCV000898159.1
First in ClinVar: Apr 22, 2019 Last updated: Apr 22, 2019 |
|
|
|
Pathogenic
(Dec 31, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 4
Affected status: yes
Allele origin:
germline
|
Baylor Genetics
Accession: SCV000992839.1
First in ClinVar: Aug 14, 2019 Last updated: Aug 14, 2019 |
|
|
|
Pathogenic
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 4
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001135658.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
|
|
|
Pathogenic
(Jun 17, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 4
Affected status: yes
Allele origin:
de novo
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001429163.1
First in ClinVar: Aug 15, 2020 Last updated: Aug 15, 2020 |
Comment:
This variant was identified as de novo (maternity and paternity confirmed).
Number of individuals with the variant: 1
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: research
|
Hereditary spastic paraplegia 4
Affected status: yes
Allele origin:
maternal
|
National Institute of Neuroscience, National Center of Neurology and Psychiatry
Accession: SCV001438322.1
First in ClinVar: Mar 12, 2021 Last updated: Mar 12, 2021 |
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446399.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Sex: male
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 4
Affected status: yes
Allele origin:
unknown
|
Paris Brain Institute, Inserm - ICM
Accession: SCV001450999.1
First in ClinVar: May 16, 2021 Last updated: May 16, 2021 |
Number of individuals with the variant: 3
|
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 4
Affected status: yes
Allele origin:
unknown
|
Neurogenetics Laboratory, Gh Pitie Salpetriere Aphp
Accession: SCV001481803.1
First in ClinVar: Feb 27, 2021 Last updated: Feb 27, 2021
Comment:
mosaic symptomatic carrier
|
Clinical Features:
Progressive spastic paraplegia (present)
|
|
|
Pathogenic
(May 12, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001715442.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Comment:
PS4, PM1, PM2, PM5, PM6, PP1
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Jul 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Abnormal central motor function
Affected status: yes
Allele origin:
germline
|
Kariminejad - Najmabadi Pathology & Genetics Center
Accession: SCV001755260.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
|
|
|
Pathogenic
(Jan 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 4
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002058176.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 29421991, 27260292, 16009769, 16055926, PS4_S). The variant has been previously reported as de … (more)
The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 29421991, 27260292, 16009769, 16055926, PS4_S). The variant has been previously reported as de novo in a similarly affected individual (PMID: 29421991, PS2_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000005660,VCV000801664, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.986, 3CNET: 0.998, PP3_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Global developmental delay (present) , Microcephaly (present) , Spastic paraplegia (present)
|
|
|
Pathogenic
(Sep 23, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 4
Affected status: yes
Allele origin:
de novo
|
Centogene AG - the Rare Disease Company
Accession: SCV002059652.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
|
|
|
Pathogenic
(Dec 16, 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: SCV002105613.1
First in ClinVar: Mar 19, 2022 Last updated: Mar 19, 2022 |
|
|
|
Pathogenic
(Aug 12, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 4
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV000680389.3
First in ClinVar: Feb 08, 2018 Last updated: Dec 24, 2022 |
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Global developmental delay (present) , Spasticity (present) , Dystonic disorder (present) , Intellectual disability (present)
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Spasticity (present) , Dystonic disorder (present)
Observation 3:
Number of individuals with the variant: 1
Clinical Features:
Spasticity (present) , Dysarthria (present) , Spastic tetraparesis (present) , Hypomimic face (present)
|
|
|
Pathogenic
(Mar 31, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 4
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002766730.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant Negative and loss-of-function are known mechanisms … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant Negative and loss-of-function are known mechanisms of disease for this gene and are associated with spastic paraplegia 4 (MIM#182601). Multiple loss of function variants have been reported, while a dominant negative mechanism has been associated with a small number of missense variants (ClinVar; PMID: 30006150). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance, but is mostly age-dependant penetrance and only a small proportion of individuals remain asymptomatic (PMID: 30476002). (I) 0115 - Variants in this gene are known to have variable expressivity, with variable age of onset and disease severity (PMID: 30476002). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It is a recurrent variant in individuals with spastic paraplegia, often occured de novo and has highly variable expressivity (ClinVar, DECIPHER, PMID: 34753439). (SP) 0600 - Variant is located in the annotated AAA domain (DECIPHER). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
|
|
Likely pathogenic
(Mar 17, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000741401.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Spastic paraparesis (present) , Cognitive impairment (present) , Spasticity (present) , Strabismus (present) , Chronic constipation (present) , Overbite (present) , High, narrow palate (present) … (more)
Spastic paraparesis (present) , Cognitive impairment (present) , Spasticity (present) , Strabismus (present) , Chronic constipation (present) , Overbite (present) , High, narrow palate (present) , Malar prominence (present) , Long face (present) , Epicanthus (present) , Micrognathia (present) , Tapered finger (present) , Joint hypermobility (present) , Prominent fingertip pads (present) , Broad nail (present) , Muscle weakness (present) , Brisk reflexes (present) , Ankle clonus (present) , Muscular hypotonia (present) , Neurodevelopmental delay (present) (less)
Sex: female
Ethnicity/Population group: Caucasian
|
|
|
Pathogenic
(Jul 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001751731.3
First in ClinVar: Jul 18, 2021 Last updated: Mar 04, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27260292, 16009769, 29761117, 29421991, 29980238, 30564185, 31486053, 31157359, 31227335, 30476002, 31216405, 31698101, 31031587, 33098801, 33624935) (less)
|
|
|
Pathogenic
(Aug 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 4
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV003808093.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
ACMG classification criteria: PS3 supporting, PS4 strong, PM1 moderated, PM2 moderated, PM6 moderated, PP3 supporting
Number of individuals with the variant: 1
Clinical Features:
Dysarthria (present) , Spastic paraplegia (present) , Cerebellar ataxia (present)
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
|
|
|
Pathogenic
(Mar 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
SPAST-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004116580.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The SPAST c.1496G>A variant is predicted to result in the amino acid substitution p.Arg499His. This variant has not been reported in a large population database … (more)
The SPAST c.1496G>A variant is predicted to result in the amino acid substitution p.Arg499His. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It has been reported in multiple patients with autosomal dominant spastic paraplegia (Depienne et al. 2006. PubMed ID: 16055926; Shoukier et al. 2009. PubMed ID: 18701882; de Bot et al. 2010. PubMed ID: 20562464; Kim et al. 2014. PubMed ID: 25045380; Polymeris et al. 2016. PubMed ID: 27260292). A different substitution affecting the same amino acid residue (p.Arg499Cys) has also been reported to be pathogenic for autosomal dominant spastic paraplegia (Depienne et al. 2006. PubMed ID: 16055926, Hazan et al. 1999. PubMed ID: 10610178; Evans et al. 2005. PubMed ID: 15716377; Shoukier et al. 2009. PubMed ID: 18701882). Taken together, we interpret the c.1496G>A (p.Arg499His) variant as pathogenic. (less)
|
|
|
Pathogenic
(Jan 13, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 4
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000290034.9
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 499 of the SPAST protein (p.Arg499His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 499 of the SPAST protein (p.Arg499His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary spastic paraplegia 4 (PMID: 16009769, 16055926, 16682546, 18701882, 20562464). ClinVar contains an entry for this variant (Variation ID: 240950). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Arg499 amino acid residue in SPAST. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15095758, 15716377). 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. (less)
|
|
|
Pathogenic
(Sep 26, 2019)
|
no assertion criteria provided
Method: clinical testing
|
Hereditary spastic paraplegia 4
Affected status: yes
Allele origin:
germline
|
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001133115.1
First in ClinVar: Jan 06, 2020 Last updated: Jan 06, 2020 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001958181.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
Pathogenic
(Dec 01, 2022)
|
no assertion criteria provided
Method: clinical testing
|
Hereditary spastic paraplegia 4
Affected status: yes
Allele origin:
germline
|
Human Genetics, University of Luebeck
Accession: SCV003834786.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
|
|
|
Uncertain significance
(Jan 29, 2016)
|
Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000339060.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
| click to load more click to collapse | |||||
| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
PS4, PM1, PM2, PM5, PM6, PP1
Comment:
The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 29421991, 27260292, 16009769, 16055926, PS4_S). The variant has been previously reported as de novo in a similarly affected individual (PMID: 29421991, PS2_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000005660,VCV000801664, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.986, 3CNET: 0.998, PP3_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant Negative and loss-of-function are known mechanisms of disease for this gene and are associated with spastic paraplegia 4 (MIM#182601). Multiple loss of function variants have been reported, while a dominant negative mechanism has been associated with a small number of missense variants (ClinVar; PMID: 30006150). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance, but is mostly age-dependant penetrance and only a small proportion of individuals remain asymptomatic (PMID: 30476002). (I) 0115 - Variants in this gene are known to have variable expressivity, with variable age of onset and disease severity (PMID: 30476002). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It is a recurrent variant in individuals with spastic paraplegia, often occured de novo and has highly variable expressivity (ClinVar, DECIPHER, PMID: 34753439). (SP) 0600 - Variant is located in the annotated AAA domain (DECIPHER). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27260292, 16009769, 29761117, 29421991, 29980238, 30564185, 31486053, 31157359, 31227335, 30476002, 31216405, 31698101, 31031587, 33098801, 33624935)
Comment:
ACMG classification criteria: PS3 supporting, PS4 strong, PM1 moderated, PM2 moderated, PM6 moderated, PP3 supporting
Comment:
The SPAST c.1496G>A variant is predicted to result in the amino acid substitution p.Arg499His. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It has been reported in multiple patients with autosomal dominant spastic paraplegia (Depienne et al. 2006. PubMed ID: 16055926; Shoukier et al. 2009. PubMed ID: 18701882; de Bot et al. 2010. PubMed ID: 20562464; Kim et al. 2014. PubMed ID: 25045380; Polymeris et al. 2016. PubMed ID: 27260292). A different substitution affecting the same amino acid residue (p.Arg499Cys) has also been reported to be pathogenic for autosomal dominant spastic paraplegia (Depienne et al. 2006. PubMed ID: 16055926, Hazan et al. 1999. PubMed ID: 10610178; Evans et al. 2005. PubMed ID: 15716377; Shoukier et al. 2009. PubMed ID: 18701882). Taken together, we interpret the c.1496G>A (p.Arg499His) variant as pathogenic.
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 499 of the SPAST protein (p.Arg499His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary spastic paraplegia 4 (PMID: 16009769, 16055926, 16682546, 18701882, 20562464). ClinVar contains an entry for this variant (Variation ID: 240950). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Arg499 amino acid residue in SPAST. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15095758, 15716377). 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.
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:
This variant was identified as de novo (maternity and paternity confirmed).
Comment:
PS4, PM1, PM2, PM5, PM6, PP1
Comment:
The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 29421991, 27260292, 16009769, 16055926, PS4_S). The variant has been previously reported as de novo in a similarly affected individual (PMID: 29421991, PS2_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000005660,VCV000801664, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.986, 3CNET: 0.998, PP3_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant Negative and loss-of-function are known mechanisms of disease for this gene and are associated with spastic paraplegia 4 (MIM#182601). Multiple loss of function variants have been reported, while a dominant negative mechanism has been associated with a small number of missense variants (ClinVar; PMID: 30006150). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance, but is mostly age-dependant penetrance and only a small proportion of individuals remain asymptomatic (PMID: 30476002). (I) 0115 - Variants in this gene are known to have variable expressivity, with variable age of onset and disease severity (PMID: 30476002). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It is a recurrent variant in individuals with spastic paraplegia, often occured de novo and has highly variable expressivity (ClinVar, DECIPHER, PMID: 34753439). (SP) 0600 - Variant is located in the annotated AAA domain (DECIPHER). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27260292, 16009769, 29761117, 29421991, 29980238, 30564185, 31486053, 31157359, 31227335, 30476002, 31216405, 31698101, 31031587, 33098801, 33624935)
Comment:
ACMG classification criteria: PS3 supporting, PS4 strong, PM1 moderated, PM2 moderated, PM6 moderated, PP3 supporting
Comment:
The SPAST c.1496G>A variant is predicted to result in the amino acid substitution p.Arg499His. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It has been reported in multiple patients with autosomal dominant spastic paraplegia (Depienne et al. 2006. PubMed ID: 16055926; Shoukier et al. 2009. PubMed ID: 18701882; de Bot et al. 2010. PubMed ID: 20562464; Kim et al. 2014. PubMed ID: 25045380; Polymeris et al. 2016. PubMed ID: 27260292). A different substitution affecting the same amino acid residue (p.Arg499Cys) has also been reported to be pathogenic for autosomal dominant spastic paraplegia (Depienne et al. 2006. PubMed ID: 16055926, Hazan et al. 1999. PubMed ID: 10610178; Evans et al. 2005. PubMed ID: 15716377; Shoukier et al. 2009. PubMed ID: 18701882). Taken together, we interpret the c.1496G>A (p.Arg499His) variant as pathogenic.
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 499 of the SPAST protein (p.Arg499His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary spastic paraplegia 4 (PMID: 16009769, 16055926, 16682546, 18701882, 20562464). ClinVar contains an entry for this variant (Variation ID: 240950). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Arg499 amino acid residue in SPAST. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15095758, 15716377). 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| A p.Arg499His mutation in SPAST is associated with infantile-onset complicated spastic paraplegia: a case report and review of the literature. | Nan H | BMC neurology | 2021 | PMID: 34753439 |
| Whole genome sequencing of 45 Japanese patients with intellectual disability. | Abe-Hatano C | American journal of medical genetics. Part A | 2021 | PMID: 33624935 |
| Next Generation Molecular Diagnosis of Hereditary Spastic Paraplegias: An Italian Cross-Sectional Study. | D'Amore A | Frontiers in neurology | 2018 | PMID: 30564185 |
| 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 |
| Clinical spectrum and genetic landscape for hereditary spastic paraplegias in China. | Dong EL | Molecular neurodegeneration | 2018 | PMID: 29980238 |
| Genomic analysis identifies masqueraders of full-term cerebral palsy. | Takezawa Y | Annals of clinical and translational neurology | 2018 | PMID: 29761117 |
| Association of Early-Onset Spasticity and Risk for Cognitive Impairment With Mutations at Amino Acid 499 in SPAST. | Gillespie MK | Journal of child neurology | 2018 | PMID: 29421991 |
| Risk Factors for Dystonia after Selective Dorsal Rhizotomy in Nonwalking Children and Adolescents with Bilateral Spasticity. | van de Pol LA | Neuropediatrics | 2018 | PMID: 29112992 |
| Infantile-onset ascending spastic paraplegia phenotype associated with SPAST mutation. | de Souza PV | Journal of the neurological sciences | 2016 | PMID: 27871443 |
| A series of Greek children with pure hereditary spastic paraplegia: clinical features and genetic findings. | Polymeris AA | Journal of neurology | 2016 | PMID: 27260292 |
| Mutation analysis of SPAST, ATL1, and REEP1 in Korean Patients with Hereditary Spastic Paraplegia. | Kim TH | Journal of clinical neurology (Seoul, Korea) | 2014 | PMID: 25045380 |
| The AAA ATPase spastin links microtubule severing to membrane modelling. | Lumb JH | Biochimica et biophysica acta | 2012 | PMID: 21888932 |
| Hereditary spastic paraplegia due to SPAST mutations in 151 Dutch patients: new clinical aspects and 27 novel mutations. | de Bot ST | Journal of neurology, neurosurgery, and psychiatry | 2010 | PMID: 20562464 |
| 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 |
| Structural basis of microtubule severing by the hereditary spastic paraplegia protein spastin. | Roll-Mecak A | Nature | 2008 | PMID: 18202664 |
| 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 |
| Mutation analysis of SPG4 and SPG3A genes and its implication in molecular diagnosis of Korean patients with hereditary spastic paraplegia. | Park SY | Archives of neurology | 2005 | PMID: 16009769 |
| Linking axonal degeneration to microtubule remodeling by Spastin-mediated microtubule severing. | Evans KJ | The Journal of cell biology | 2005 | PMID: 15716377 |
| Conserved arginine residues implicated in ATP hydrolysis, nucleotide-sensing, and inter-subunit interactions in AAA and AAA+ ATPases. | Ogura T | Journal of structural biology | 2004 | PMID: 15095758 |
| 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 |
| Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia. | Hazan J | Nature genetics | 1999 | PMID: 10610178 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SPAST | - | - | - | - |
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Text-mined citations for rs878854991 ...
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Record last updated Sep 29, 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.