This sequence change affects a donor splice site in intron 2 of the SPG11 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SPG11 are known to be pathogenic (PMID: 19105190, 20110243, 22154821, 26556829). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1114). Disruption of this splice site has been observed in individuals with hereditary spastic paraplegia (PMID: 18067136, 20390432, 23733235, 33084218). This variant is present in population databases (rs312262715, gnomAD 0.0009%).
ClinVar Genomic variation as it relates to human health
NM_025137.4(SPG11):c.442+1G>C
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
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_025137.4(SPG11):c.442+1G>C
Variation ID: 1114 Accession: VCV000001114.39
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q21.1 15: 44660431 (GRCh38) [ NCBI UCSC ] 15: 44952629 (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 May 3, 2013 Oct 20, 2024 May 23, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_025137.4:c.442+1G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001160227.2:c.442+1G>C splice donor NM_001411132.1:c.442+1G>C splice donor NC_000015.10:g.44660431C>G NC_000015.9:g.44952629C>G NG_008885.1:g.8248G>C - Protein change
- -
- Other names
-
IVS2DS, G-C, +1
- Canonical SPDI
- NC_000015.10:44660430:C:G
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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. |
|||
| SPG11 | - | - |
GRCh38 GRCh37 |
3265 | 3367 | |
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 (6) |
criteria provided, multiple submitters, no conflicts
|
Dec 20, 2022 | RCV000001173.16 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 1, 2020 | RCV001092501.23 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 23, 2024 | RCV004689398.1 |
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 20, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 11
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001209402.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects a donor splice site in intron 2 of the SPG11 gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects a donor splice site in intron 2 of the SPG11 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SPG11 are known to be pathogenic (PMID: 19105190, 20110243, 22154821, 26556829). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1114). Disruption of this splice site has been observed in individuals with hereditary spastic paraplegia (PMID: 18067136, 20390432, 23733235, 33084218). This variant is present in population databases (rs312262715, gnomAD 0.0009%). (less)
|
|
|
Pathogenic
(Jan 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 11
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002058850.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are … (more)
Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_VS).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000001114).It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2_M). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (3billion dataset, PM3_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Cerebellar ataxia (present) , Intellectual disability (present)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 11
Affected status: unknown
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002762893.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
|
|
|
Pathogenic
(May 23, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005184983.1
First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
Comment:
Variant summary: SPG11 c.442+1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more)
Variant summary: SPG11 c.442+1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250866 control chromosomes. c.442+1G>C has been reported in the literature in individuals affected with Hereditary Spastic Paraplegia, Type 11 (Salinas_2020, Hehr_2007). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18067136, 33084218). ClinVar contains an entry for this variant (Variation ID: 1114). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Aug 01, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001249040.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 4
|
|
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Pathogenic
(Dec 01, 2007)
|
no assertion criteria provided
Method: literature only
|
SPASTIC PARAPLEGIA 11, AUTOSOMAL RECESSIVE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000021323.2
First in ClinVar: Apr 04, 2013 Last updated: Jun 18, 2015 |
Comment on evidence:
In affected members of a consanguineous Turkish family with autosomal recessive spastic paraplegia-11 (SPG11; 604360), Hehr et al. (2007) identified a homozygous G-to-C transversion in … (more)
In affected members of a consanguineous Turkish family with autosomal recessive spastic paraplegia-11 (SPG11; 604360), Hehr et al. (2007) identified a homozygous G-to-C transversion in the donor splice site of intron 2 of the SPG11 gene. The family was previously reported by Olmez et al. (2006). (less)
|
|
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Pathogenic
(Dec 27, 2023)
|
no assertion criteria provided
Method: clinical testing
|
Hereditary spastic paraplegia 11
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Razi Pathobiology & Medical Genetics
Accession: SCV004190232.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Indication for testing: suspected to hereditary spastic paraplegia
Sex: female
Geographic origin: Iran
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Hereditary spastic paraplegia 11
Affected status: not provided
Allele origin:
unknown
|
GeneReviews
Accession: SCV000058155.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
|
Comment:
Comment:
Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_VS).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000001114).It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2_M). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (3billion dataset, PM3_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
Variant summary: SPG11 c.442+1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250866 control chromosomes. c.442+1G>C has been reported in the literature in individuals affected with Hereditary Spastic Paraplegia, Type 11 (Salinas_2020, Hehr_2007). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18067136, 33084218). ClinVar contains an entry for this variant (Variation ID: 1114). Based on the evidence outlined above, the variant was 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 sequence change affects a donor splice site in intron 2 of the SPG11 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SPG11 are known to be pathogenic (PMID: 19105190, 20110243, 22154821, 26556829). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1114). Disruption of this splice site has been observed in individuals with hereditary spastic paraplegia (PMID: 18067136, 20390432, 23733235, 33084218). This variant is present in population databases (rs312262715, gnomAD 0.0009%).
Comment:
Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_VS).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000001114).It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2_M). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (3billion dataset, PM3_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
Variant summary: SPG11 c.442+1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250866 control chromosomes. c.442+1G>C has been reported in the literature in individuals affected with Hereditary Spastic Paraplegia, Type 11 (Salinas_2020, Hehr_2007). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18067136, 33084218). ClinVar contains an entry for this variant (Variation ID: 1114). Based on the evidence outlined above, the variant was classified as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| The odyssey of complex neurogenetic disorders: From undetermined to positive. | Salinas V | American journal of medical genetics. Part C, Seminars in medical genetics | 2020 | PMID: 33084218 |
| Spastic Paraplegia 11. | Adam MP | - | 2019 | PMID: 20301389 |
| ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease. | Montecchiani C | Brain : a journal of neurology | 2016 | PMID: 26556829 |
| Autosomal recessive hereditary spastic paraplegia-clinical and genetic characteristics of a well-defined cohort. | Yoon G | Neurogenetics | 2013 | PMID: 23733235 |
| Exome sequencing reveals SPG11 mutations causing juvenile ALS. | Daoud H | Neurobiology of aging | 2012 | PMID: 22154821 |
| Novel SPG11 mutations in Asian kindreds and disruption of spatacsin function in the zebrafish. | Southgate L | Neurogenetics | 2010 | PMID: 20390432 |
| SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis. | Orlacchio A | Brain : a journal of neurology | 2010 | PMID: 20110243 |
| Screening of ARHSP-TCC patients expands the spectrum of SPG11 mutations and includes a large scale gene deletion. | Denora PS | Human mutation | 2009 | PMID: 19105190 |
| Long-term course and mutational spectrum of spatacsin-linked spastic paraplegia. | Hehr U | Annals of neurology | 2007 | PMID: 18067136 |
| Further clinical and genetic characterization of SPG11: hereditary spastic paraplegia with thin corpus callosum. | Olmez A | Neuropediatrics | 2006 | PMID: 16773502 |
| Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
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Text-mined citations for rs312262715 ...
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.