SPG11

protein-coding

SPG11 vesicle trafficking associated, spatacsin

Gene summary

The protein encoded by this gene is a potential transmembrane protein that is phosphorylated upon DNA damage. Defects in this gene are a cause of spastic paraplegia type 11 (SPG11). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2009]

Previous symbols:

KIAA1840
ALS5

MANE transcript

NM_025137.4

Inheritance

ClinVar variants

P:578U:1448B:932

Top phenotype

Amyotrophic lateral sclerosis 5, juvenile recessive; Charcot-Marie-Tooth disease, axonal, type 2X; Spastic paraplegia 11, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.67

Max pathogenic AF

—

Genomic locus

chr15:44,554,818-44,663,688

External References & Databases

Ensembl (ENSG00000104133)

Transcript & Mutation Effects

hg38 • Region Span ~108.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary spastic paraplegia 11STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011445

Submitter: Genomics England PanelApp

juvenile amyotrophic lateral sclerosisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017593

Submitter: Orphanet

hereditary spastic paraplegia 11SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011445

Submitter: Orphanet

hereditary spastic paraplegia 11DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011445

Submitter: G2P

Charcot-Marie-Tooth disease axonal type 2XSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014726

Submitter: Orphanet

Charcot-Marie-Tooth disease axonal type 2XSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014726

Submitter: Genomics England PanelApp

hereditary spastic paraplegia 11DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011445

Submitter: ClinGen

*SPG11* was first reported in relation to autosomal recessive hereditary spastic paraplegia 11 (HSP11) in 2007 (HStevanin G, et al., 2007, PMID: 17322883). HSP11 is clinically characterized by the progressive spasticity of the lower limbs, thin corpus callosum and cognitive impairment. White matter alterations may be part of the clinical phenotype. HSP11 is a complex disorder that occurs along a spectrum of disease including cases with wither slowly progressive juvenile amyotrophic lateral sclerosis and Charcot-Marie-Tooth disease, due to overlapping variants with a loss of function mechanism. As per ClinGen lumping and splitting criteria, these diseases were considered under the lumped entity of HSP11. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Thirty-six variants have been curated (including frameshift, nonsense, and splice variants), from 18 probands in 3 publications (PMIDs: 17322883, 20110243, 26556829). Cosegregation of variants with disease was reported in at least 26 family members as well. Additional evidence is available in the literature but the maximum score for genetic evidence was reached. Experimentally, this gene-disease relationship is supported by its biochemical function in autophagic lysosome reformation (PMID: 25365221), which it shares with spastizin, another HSP related gene, with similarities in their expression and localization patterns that could account for their overlapping clinical phenotypes (PMID: 21545838), and is disrupted in patient cells (Renvoisé B, et al., 2014, PMID: 24999486). as a prominent guanine nucleotide exchange factor (GEF) for the small GTPase Rab5 (PMID: 12837691). A knockout mouse recapitulates the full range of symptoms associated with *SPG11* mutations observed in HSP, ALS and CMT patients (PMID: 28237315) and 2D culture systems and 3D human brain organoids have shed light on the neurodevelopmental mechanisms underlying disease pathology (PMID: 30476097). In summary, there is definitive evidence to support this gene-disease relationship.

amyotrophic lateral sclerosis type 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011196

Submitter: Labcorp Genetics (formerly Invitae)

hereditary spastic paraplegia 11STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011445

Submitter: Labcorp Genetics (formerly Invitae)

Charcot-Marie-Tooth disease axonal type 2XSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014726

Submitter: Labcorp Genetics (formerly Invitae)

amyotrophic lateral sclerosis type 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011196

Submitter: Genomics England PanelApp

hereditary spastic paraplegia 11DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011445

Submitter: Illumina

Clinical Genomic Database (CGD)

Amyotrophic lateral sclerosis 5, juvenile recessive; Charcot-Marie-Tooth disease, axonal, type 2X; Spastic paraplegia 11, autosomal recessiveAR

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 17717710; 18067136; 17322883; 18663179; 18787847; 19196735; 19194956; 19513778; 20108361; 20110243; 20301389; 20390432; 20571989; 20971220; 21035867; 21381113; 21625935; 22154821; 22175763; 23043354; 23121729; 26556829

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SPG11 variants in ClinVar

29 Conditions Cataloged

Hereditary spastic paraplegia 11Total: 3174

not providedTotal: 686

Inborn genetic diseasesTotal: 613

Amyotrophic lateral sclerosis type 5Total: 320

Charcot-Marie-Tooth disease axonal type 2XTotal: 319

Hereditary spastic paraplegiaTotal: 152

not specifiedTotal: 146

SPG11-related disorderTotal: 62

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_025137.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		2 clinvar	25 clinvar	856 clinvar	6 clinvar	889
missense	7 clinvar	11 clinvar	1375 clinvar	61 clinvar	9 clinvar	1463
nonsense	113 clinvar	48 clinvar	12 clinvar			173
start loss			1 clinvar			1
frameshift	230 clinvar	81 clinvar	27 clinvar			338
splice donor/acceptor (+/-2bp)	21 clinvar	65 clinvar	8 clinvar			94
Total	371	207	1448	917	15	2958

Highest pathogenic variant AF is 0.00017781225

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 48 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_025137.4	RefSeq	NP_079413.3	40	MANE Select
ENST00000261866.12	Ensembl	ENSP00000261866.7	40	MANE Select
NM_001160227.2	RefSeq	NP_001153699.1	38	Standard
NM_001411132.1	RefSeq	NP_001398061.1	40	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
spg11	Danio rerio	Structure: retinal ganglion cell Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

spg11

Danio rerio

Structure: retinal ganglion cell

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

chemical synaptic transmission
axo-dendritic transport
synaptic vesicle transport
axon extension
phagosome-lysosome fusion involved in apoptotic cell clearance

Molecular Function

protein binding

Cellular Component

nucleolus
cytoplasm
lysosomal membrane
cytosol
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000261866
Coding exons: 40
Length: 100983
Individuals with no LoFs: 125367
Homozygous LoFs: 0
Heterozygous LoFs: 381
Defined: 125748
p: 0.00152

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-1.39	1360	1.22e+3	1.11	0.0000609	16162
Missense (PolyPhen)		429	412.9	1.039		5520
Synonymous	-2.17	521	462	1.13	0.0000228	4514
Loss of Function	3.30	81	120	0.675	0.00000584	1505

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0014	0.0014	notable
Latino/Admixed American	0.0012	0.0012	notable
Ashkenazi Jewish	0.00099	0.00099	rare
East Asian	0.0016	0.0016	notable
Finnish	0.00065	0.00065	rare
European (Non-Finnish)	0.0019	0.0019	notable
South Asian	0.0015	0.0015	notable
Other	0.0011	0.0011	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May play a role in neurite plasticity by maintaining cytoskeleton stability and regulating synaptic vesicle transport. {ECO:0000269|PubMed:24794856}.;
Disease: DISEASE: Amyotrophic lateral sclerosis 5, juvenile (ALS5) [MIM:602099]: A form of amyotrophic lateral sclerosis, a neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5- 10% of the cases. ALS5 is an autosomal recessive, juvenile form characterized by onset of upper and lower motor neuron signs before age 25. {ECO:0000269|PubMed:20110243}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Charcot-Marie-Tooth disease 2X (CMT2X) [MIM:616668]: An autosomal recessive, axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot- Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. CMT2X patients manifest a slowly progressive, peripheral neuropathy affecting the lower limbs and resulting in gait difficulties and distal sensory impairment. Some patients also have upper limb involvement. {ECO:0000269|PubMed:26556829}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.113

Intolerance Scores

LoFtool: 0.615
RVIS EVS: -0.48
RVIS percentile EVS: 22.79

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.414

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High