VCV000041320.22 - ClinVar

NM_025137.4(SPG11):c.5255del (p.Phe1752fs)

Germline

Classification

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.

(4)

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

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.5255del (p.Phe1752fs)

Variation ID: 41320 Accession: VCV000041320.22

Type and length

Deletion, 1 bp

Location

Cytogenetic: 15q21.1 15: 44584425 (GRCh38) [ NCBI UCSC ] 15: 44876623 (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	Apr 22, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_025137.4:c.5255del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_079413.3:p.Phe1752fs	frameshift
NM_001160227.2:c.5255del	NP_001153699.1:p.Phe1752fs	frameshift
NC_000015.10:g.44584429del
NC_000015.9:g.44876627del
NG_008885.1:g.84254del

... more HGVS ... less HGVS

Protein change

F1752fs

Other names

Canonical SPDI

NC_000015.10:44584424:AAAAA:AAAA

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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

ClinGen: CA344351 dbSNP: rs312262763 VarSome

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
Gene	OMIM	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.
LOC130056971	-	-	-	GRCh38	-	23
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.
Hereditary spastic paraplegia 11	Pathogenic (2)	criteria provided, single submitter	Apr 22, 2023	RCV000034221.6
not provided	Pathogenic (1)	criteria provided, single submitter	Jun 1, 2022	RCV002262598.16
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Nov 22, 2019	RCV002336108.3

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 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002545246.16 First in ClinVar: Jul 09, 2022 Last updated: Oct 20, 2024	Comment: SPG11: PVS1, PM2 Number of individuals with the variant: 1
Pathogenic (Apr 22, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary spastic paraplegia 11 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004344921.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (6) PubMed: 18067136‚ 25769290‚ 19105190‚ 20110243‚ 22154821‚ 26556829 Comment: For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 41320). This premature translational stop signal … (more) For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 41320). This premature translational stop signal has been observed in individual(s) with clinical features of SPG11-related conditions (PMID: 18067136, 25769290). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe1752Serfs*86) 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). (less)
Pathogenic (Nov 22, 2019)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002643326.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (5) PubMed: 18067136‚ 19105190‚ 21625935‚ 25769290‚ 27180005 Comment: The c.5255delT pathogenic mutation, located in coding exon 30 of the SPG11 gene, results from a deletion of one nucleotide at nucleotide position 5255, causing … (more) The c.5255delT pathogenic mutation, located in coding exon 30 of the SPG11 gene, results from a deletion of one nucleotide at nucleotide position 5255, causing a translational frameshift with a predicted alternate stop codon (p.F1752Sfs*86). This mutation has been detected in both the heterozygous and homozygous states in individuals with hereditary spastic paraplegia (Hehr U et al. Ann. Neurol., 2007 Dec;62:656-65; Hooper AJ et al. Clin. Chim. Acta, 2015 May;445:1; Denora PS et al. Hum. Mutat., 2009 Mar;30:E500-19; Laurencin C et al. Rev. Neurol. (Paris) May;172:389-91). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
not provided (-)	no classification provided Method: literature only	Hereditary spastic paraplegia 11 Affected status: not provided Allele origin: unknown	GeneReviews Accession: SCV000058159.3 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: PubMed (3) PubMed: 18067136‚ 19105190‚ 20301389 BookShelf: NBK1210 BookShelf: NBK1210

Comment:

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 41320). This premature translational stop signal has been observed in individual(s) with clinical features of SPG11-related conditions (PMID: 18067136, 25769290). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe1752Serfs*86) 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).

Comment:

The c.5255delT pathogenic mutation, located in coding exon 30 of the SPG11 gene, results from a deletion of one nucleotide at nucleotide position 5255, causing a translational frameshift with a predicted alternate stop codon (p.F1752Sfs*86). This mutation has been detected in both the heterozygous and homozygous states in individuals with hereditary spastic paraplegia (Hehr U et al. Ann. Neurol., 2007 Dec;62:656-65; Hooper AJ et al. Clin. Chim. Acta, 2015 May;445:1; Denora PS et al. Hum. Mutat., 2009 Mar;30:E500-19; Laurencin C et al. Rev. Neurol. (Paris) May;172:389-91). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Spastic Paraplegia 11.	Adam MP	-	2019	PMID: 20301389
A rare case of SPG11 mutation with multiple sclerosis.	Laurencin C	Revue neurologique	2016	PMID: 27180005
ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease.	Montecchiani C	Brain : a journal of neurology	2016	PMID: 26556829
SPG11 mutation in a Turkish familial hypobetalipoproteinemia family with hereditary spastic paraplegia.	Hooper AJ	Clinica chimica acta; international journal of clinical chemistry	2015	PMID: 25769290
Exome sequencing reveals SPG11 mutations causing juvenile ALS.	Daoud H	Neurobiology of aging	2012	PMID: 22154821
Structural and metabolic damage in brains of patients with SPG11-related spastic paraplegia as detected by quantitative MRI.	Stromillo ML	Journal of neurology	2011	PMID: 21625935
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

Text-mined citations for rs312262763 ...

These 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

ClinVar Genomic variation as it relates to human health

NM_025137.4(SPG11):c.5255del (p.Phe1752fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs312262763 ...