Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18717728, 26971897, 30574063, 20110243, 18067136)
ClinVar Genomic variation as it relates to human health
NM_025137.4(SPG11):c.267G>A (p.Trp89Ter)
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.
(11)
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
11
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.267G>A (p.Trp89Ter)
Variation ID: 41294 Accession: VCV000041294.27
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 15q21.1 15: 44660607 (GRCh38) [ NCBI UCSC ] 15: 44952805 (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 Mar 2, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_025137.4:c.267G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_079413.3:p.Trp89Ter nonsense NM_001160227.2:c.267G>A NP_001153699.1:p.Trp89Ter nonsense NC_000015.10:g.44660607C>T NC_000015.9:g.44952805C>T NG_008885.1:g.8072G>A - Protein change
- W89*
- Other names
-
p.Trp89Ter
- Canonical SPDI
- NC_000015.10:44660606:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
protein truncation; Variation Ontology [ VariO:0015]
-
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 |
3254 | 3355 | |
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 21, 2023 | RCV000034195.18 | |
| Pathogenic (1) |
no assertion criteria provided
|
Feb 1, 2010 | RCV000194703.2 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 1, 2024 | RCV001569808.13 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 2, 2024 | RCV003883485.2 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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
(Mar 10, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001793962.3
First in ClinVar: Aug 21, 2021 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18717728, 26971897, 30574063, 20110243, 18067136) (less)
|
|
|
Pathogenic
(Dec 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 11
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000823331.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Trp89*) in the SPG11 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Trp89*) in the SPG11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPG11 are known to be pathogenic (PMID: 19105190, 20110243, 22154821, 26556829). This variant is present in population databases (rs312262709, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with hereditary spastic paraplegia or juvenile amyotrophic lateral sclerosis (PMID: 18067136, 20110243, 27217339). ClinVar contains an entry for this variant (Variation ID: 41294). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Sep 23, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 11
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV002600276.1
First in ClinVar: Dec 03, 2022 Last updated: Dec 03, 2022 |
Comment:
A homozygous nonsense variation in exon 2 of the SPG11 gene that results in a stop codon and premature truncation of the protein at codon … (more)
A homozygous nonsense variation in exon 2 of the SPG11 gene that results in a stop codon and premature truncation of the protein at codon 89 was detected . This variant has not been reported in the 1000 genomes and gnomAD databases . The in silico prediction# of the variant is damaging by MutationTaster2. The reference codon is conserved across species. (less)
Clinical Features:
Poor speech (present) , Difficulty walking (present)
Age: 10-19 years
Sex: male
Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
|
|
|
Pathogenic
(Mar 02, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Charcot-Marie-Tooth disease axonal type 2X
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV004697930.1
First in ClinVar: Mar 10, 2024 Last updated: Mar 10, 2024 |
Comment:
A homozygous nonsense variant in exon 2 of the SPG11 gene that results in a stop codon and premature truncation of the protein at codon … (more)
A homozygous nonsense variant in exon 2 of the SPG11 gene that results in a stop codon and premature truncation of the protein at codon 89 (p.Trp89Ter) was detected. The observed variant has previously been reported in patients affected with hereditary spastic paraplegia [PMID: 27217339]. This variant has not been reported in the 1000 genomes, gnomAD (v3.1), gnomdAD (v2.1) and topmed databases. The in-silico prediction of the variant is damaging by MutationTaster2. The reference codon is conserved across mammals. In summary, the variant meets our criteria to be classified as pathogenic. (less)
Clinical Features:
Difficulty walking (present) , Difficulty climbing stairs (present) , Tip-toe gait (present)
Age: 20-29 years
Sex: male
Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on the Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
|
|
|
Pathogenic
(Feb 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004704265.8
First in ClinVar: Mar 10, 2024 Last updated: Oct 20, 2024 |
Comment:
SPG11: PVS1, PM2, PM3
Number of individuals with the variant: 1
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 11
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004046965.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The stop gained variant c.267G>A (p.Trp89Ter) in SPG11 gene has been observed to be homozygous or in combination with another SPG11 variant in individuals affected … (more)
The stop gained variant c.267G>A (p.Trp89Ter) in SPG11 gene has been observed to be homozygous or in combination with another SPG11 variant in individuals affected with hereditary spastic paraplegia or juvenile amyotrophic lateral sclerosis (Orlacchio A et.al.,2010). This variant has been reported to the ClinVar database as Pathogenic. The variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.0003982% is reported in gnomAD. Loss-of-function variants in SPG11 are known to be pathogenic. The nucleotide change in SPG11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic . (less)
Clinical Features:
Intellectual disability (present) , Peripheral neuropathy (present) , Pseudobulbar signs (present) , Thin corpus callosum (present)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Charcot-Marie-Tooth disease axonal type 2X
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV005073928.1
First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024 |
Comment:
The observed stop gained variant c.267G>A (p.Trp89Ter) in SPG11 gene has been reported in homozygous and compound heterozygous state in individuals affected with Charcot-Marie-Tooth disease … (more)
The observed stop gained variant c.267G>A (p.Trp89Ter) in SPG11 gene has been reported in homozygous and compound heterozygous state in individuals affected with Charcot-Marie-Tooth disease (Montecchiani C et al. 2016). The p.Trp89Ter variant has allele frequency 0.0004% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submitters). The nucleotide change c.267G>A in SPG11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Loss-of-function variants in SPG11 are known to be pathogenic (Denora PS et al. 2009). This variant is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Dec 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 11
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005086076.1
First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hereditary spastic paraplegia 11 (HSP; MONDO#0011445). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 1 heterozygote, 0 homozygotes). (SP) 0701 - Other NMD-predicted variant comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in individuals, both as homozygotes and compound heterozygotes, with HSP (PMID: 35906604) and classified as pathogenic by diagnostic laboratories in ClinVar. (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 11
Affected status: unknown
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002762905.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
|
|
|
Pathogenic
(Feb 01, 2010)
|
no assertion criteria provided
Method: literature only
|
AMYOTROPHIC LATERAL SCLEROSIS 5, JUVENILE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000249580.2
First in ClinVar: Oct 05, 2015 Last updated: Oct 11, 2015 |
Comment on evidence:
For discussion of the c.267G-A transition in exon 2 of the SPG11 gene resulting in a trp89-to-ter (W89X) substitution that was found in compound heterozygous … (more)
For discussion of the c.267G-A transition in exon 2 of the SPG11 gene resulting in a trp89-to-ter (W89X) substitution that was found in compound heterozygous state in 2 Italian sisters with a protracted course of autosomal recessive juvenile amyotrophic lateral sclerosis-5 (ALS5; 602099) by Orlacchio et al. (2010), see 610844.0003. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Hereditary spastic paraplegia 11
Affected status: not provided
Allele origin:
unknown
|
GeneReviews
Accession: SCV000058133.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Trp89*) in the SPG11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPG11 are known to be pathogenic (PMID: 19105190, 20110243, 22154821, 26556829). This variant is present in population databases (rs312262709, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with hereditary spastic paraplegia or juvenile amyotrophic lateral sclerosis (PMID: 18067136, 20110243, 27217339). ClinVar contains an entry for this variant (Variation ID: 41294). For these reasons, this variant has been classified as Pathogenic.
Comment:
A homozygous nonsense variation in exon 2 of the SPG11 gene that results in a stop codon and premature truncation of the protein at codon 89 was detected . This variant has not been reported in the 1000 genomes and gnomAD databases . The in silico prediction# of the variant is damaging by MutationTaster2. The reference codon is conserved across species.
Comment:
A homozygous nonsense variant in exon 2 of the SPG11 gene that results in a stop codon and premature truncation of the protein at codon 89 (p.Trp89Ter) was detected. The observed variant has previously been reported in patients affected with hereditary spastic paraplegia [PMID: 27217339]. This variant has not been reported in the 1000 genomes, gnomAD (v3.1), gnomdAD (v2.1) and topmed databases. The in-silico prediction of the variant is damaging by MutationTaster2. The reference codon is conserved across mammals. In summary, the variant meets our criteria to be classified as pathogenic.
Comment:
SPG11: PVS1, PM2, PM3
Comment:
The stop gained variant c.267G>A (p.Trp89Ter) in SPG11 gene has been observed to be homozygous or in combination with another SPG11 variant in individuals affected with hereditary spastic paraplegia or juvenile amyotrophic lateral sclerosis (Orlacchio A et.al.,2010). This variant has been reported to the ClinVar database as Pathogenic. The variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.0003982% is reported in gnomAD. Loss-of-function variants in SPG11 are known to be pathogenic. The nucleotide change in SPG11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic .
Comment:
The observed stop gained variant c.267G>A (p.Trp89Ter) in SPG11 gene has been reported in homozygous and compound heterozygous state in individuals affected with Charcot-Marie-Tooth disease (Montecchiani C et al. 2016). The p.Trp89Ter variant has allele frequency 0.0004% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submitters). The nucleotide change c.267G>A in SPG11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Loss-of-function variants in SPG11 are known to be pathogenic (Denora PS et al. 2009). This variant is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hereditary spastic paraplegia 11 (HSP; MONDO#0011445). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 1 heterozygote, 0 homozygotes). (SP) 0701 - Other NMD-predicted variant comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in individuals, both as homozygotes and compound heterozygotes, with HSP (PMID: 35906604) and classified as pathogenic by diagnostic laboratories in ClinVar. (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|---|---|---|---|
|
protein truncation
|
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV002600276.1
|
|
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18717728, 26971897, 30574063, 20110243, 18067136)
Comment:
This sequence change creates a premature translational stop signal (p.Trp89*) in the SPG11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPG11 are known to be pathogenic (PMID: 19105190, 20110243, 22154821, 26556829). This variant is present in population databases (rs312262709, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with hereditary spastic paraplegia or juvenile amyotrophic lateral sclerosis (PMID: 18067136, 20110243, 27217339). ClinVar contains an entry for this variant (Variation ID: 41294). For these reasons, this variant has been classified as Pathogenic.
Comment:
A homozygous nonsense variation in exon 2 of the SPG11 gene that results in a stop codon and premature truncation of the protein at codon 89 was detected . This variant has not been reported in the 1000 genomes and gnomAD databases . The in silico prediction# of the variant is damaging by MutationTaster2. The reference codon is conserved across species.
Comment:
A homozygous nonsense variant in exon 2 of the SPG11 gene that results in a stop codon and premature truncation of the protein at codon 89 (p.Trp89Ter) was detected. The observed variant has previously been reported in patients affected with hereditary spastic paraplegia [PMID: 27217339]. This variant has not been reported in the 1000 genomes, gnomAD (v3.1), gnomdAD (v2.1) and topmed databases. The in-silico prediction of the variant is damaging by MutationTaster2. The reference codon is conserved across mammals. In summary, the variant meets our criteria to be classified as pathogenic.
Comment:
SPG11: PVS1, PM2, PM3
Comment:
The stop gained variant c.267G>A (p.Trp89Ter) in SPG11 gene has been observed to be homozygous or in combination with another SPG11 variant in individuals affected with hereditary spastic paraplegia or juvenile amyotrophic lateral sclerosis (Orlacchio A et.al.,2010). This variant has been reported to the ClinVar database as Pathogenic. The variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.0003982% is reported in gnomAD. Loss-of-function variants in SPG11 are known to be pathogenic. The nucleotide change in SPG11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic .
Comment:
The observed stop gained variant c.267G>A (p.Trp89Ter) in SPG11 gene has been reported in homozygous and compound heterozygous state in individuals affected with Charcot-Marie-Tooth disease (Montecchiani C et al. 2016). The p.Trp89Ter variant has allele frequency 0.0004% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submitters). The nucleotide change c.267G>A in SPG11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Loss-of-function variants in SPG11 are known to be pathogenic (Denora PS et al. 2009). This variant is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hereditary spastic paraplegia 11 (HSP; MONDO#0011445). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 1 heterozygote, 0 homozygotes). (SP) 0701 - Other NMD-predicted variant comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in individuals, both as homozygotes and compound heterozygotes, with HSP (PMID: 35906604) and classified as pathogenic by diagnostic laboratories in ClinVar. (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Neuropsychology and MRI correlates of neurodegeneration in SPG11 hereditary spastic paraplegia. | Utz KS | Orphanet journal of rare diseases | 2022 | PMID: 35906604 |
| Spastic Paraplegia 11. | Adam MP | - | 2019 | PMID: 20301389 |
| Genetic and phenotypic characterization of complex hereditary spastic paraplegia. | Kara E | Brain : a journal of neurology | 2016 | PMID: 27217339 |
| ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease. | Montecchiani C | Brain : a journal of neurology | 2016 | PMID: 26556829 |
| Exome sequencing reveals SPG11 mutations causing juvenile ALS. | Daoud H | Neurobiology of aging | 2012 | PMID: 22154821 |
| 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 |
| Clinical heterogeneity and genotype-phenotype correlations in hereditary spastic paraplegia because of Spatacsin mutations (SPG11). | Paisan-Ruiz C | European journal of neurology | 2008 | PMID: 18717728 |
| Long-term course and mutational spectrum of spatacsin-linked spastic paraplegia. | Hehr U | Annals of neurology | 2007 | PMID: 18067136 |
Text-mined citations for rs312262709 ...
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.