ATL1

protein-coding

atlastin GTPase 1, the group of Atlastins

Gene summary

The protein encoded by this gene is a GTPase and a Golgi body transmembrane protein. The encoded protein can form a homotetramer and has been shown to interact with spastin and with mitogen-activated protein kinase kinase kinase kinase 4. This protein may be involved in axonal maintenance as evidenced by the fact that defects in this gene are a cause of spastic paraplegia type 3. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Previous symbols:

SPG3
SPG3A

MANE transcript

NM_015915.5

Inheritance

AD, AR, SD

ClinVar variants

P:124U:289B:115

Top phenotype

Neuropathy, hereditary sensory, type 1D; Spastic paraplegia 3, autosomal dominant

gnomAD constraint

pLI —, LoF o/e 0.15

Max pathogenic AF

—

Genomic locus

chr14:50,532,509-50,634,017

External References & Databases

Ensembl (ENSG00000198513)

Transcript & Mutation Effects

hg38 • Region Span ~101.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neuropathy, hereditary sensory, type 1DDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013381

Submitter: ClinGen

ATL1 has first been described in the context of autosomal dominant hereditary spastic paraplegia (HSP; PMIDs: 11685207, 12112092, 12499504, 12939451, 15596607, etc.). Encoding a homo-oligomeric GTPase, it is known to be responsible for shaping the tubular structure of the endoplasmic reticulum (PMID: 27339937). In three families presenting with severe sensory neuropathy and foot ulcerations in an autosomal dominant pedigree, Guelly et al. described co-segregating variants in ATL1, one of which recurrently described in another publication, but in the same population (PMID: 22340599). Both genetic (LOD scores 2.94 and 3.31) and functional evidence (disturbed GTPase function and ER structure) on the variant level, support the assumption that these variants are responsible for the patients’ phenotype. Clinically, the authors describe a notable overlap with the HSP phenotype, which is supported by the fact that both phenotypes, neuropathy and HSP, are associated with these variants in the ClinVar database. In HSP cases, on the other hand, neuropathy seems to be a common feature as well, pointing towards an inseparable overlap between those two phenotypes. Functional evidence on ATL1, including studies on protein expression, biochemical function, and model organisms (drosophila and zebrafish) support the gene-disease relationship, which is, however, not specific for the neuropathy phenotype. The expert panel concludes that HSAN1D is part of an axonopathy spectrum definitively associated with ATL1 that mainly manifests with HSP as the leading phenotype. As neuropathy can still be an early or even leading symptom in rare constellations, we recommend that ATL1 should be implemented on both HSP and neuropathy panels.

hereditary spastic paraplegia 3ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008437

Submitter: PanelApp Australia

neuropathy, hereditary sensory, type 1DSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013381

Submitter: PanelApp Australia

hereditary sensory and autonomic neuropathy type 1SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018213

Submitter: Orphanet

hereditary spastic paraplegia 3ADEFINITIVE

Inheritance Pattern: SD

Disease ID:MONDO:0008437

Submitter: Ambry Genetics

neuropathy, hereditary sensory, type 1DSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013381

Submitter: Labcorp Genetics (formerly Invitae)

hereditary spastic paraplegia 3ASTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008437

Submitter: Labcorp Genetics (formerly Invitae)

neuropathy, hereditary sensory, type 1DMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0013381

Submitter: Ambry Genetics

hereditary spastic paraplegia 3ADEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008437

Submitter: G2P

hereditary spastic paraplegia 3ASUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008437

Submitter: Orphanet

Clinical Genomic Database (CGD)

Neuropathy, hereditary sensory, type 1D; Spastic paraplegia 3, autosomal dominantAD

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

Comments: Congenital insensitivity to pain can result in injuries and infections

Refs: 11685207; 12112092; 15517445; 15596607; 16401858; 16533974; 17502470; 21194679; 21336785; 24473461

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ATL1 variants in ClinVar

20 Conditions Cataloged

Hereditary spastic paraplegia 3ATotal: 507

not providedTotal: 189

Inborn genetic diseasesTotal: 93

ATL1-related disorderTotal: 46

not specifiedTotal: 35

Neuropathy, hereditary sensory, type 1DTotal: 33

Hereditary spastic paraplegiaTotal: 18

Spastic paraplegiaTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015915.5. 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		1 clinvar	1 clinvar	102 clinvar	1 clinvar	105
missense	25 clinvar	73 clinvar	270 clinvar	12 clinvar		380
nonsense	8 clinvar	2 clinvar	4 clinvar			14
start loss						0
frameshift	5 clinvar	6 clinvar	6 clinvar			17
splice donor/acceptor (+/-2bp)	1 clinvar	3 clinvar	8 clinvar			12
Total	39	85	289	114	1	528

Highest pathogenic variant AF is 0.000016108486

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 37 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015915.5	RefSeq	NP_056999.2	14	MANE Select
ENST00000358385.12	Ensembl	ENSP00000351155.7	14	MANE Select
NM_001127713.1	RefSeq	NP_001121185.1	13	Standard
NM_181598.4	RefSeq	NP_853629.2	13	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
atl1	Danio rerio	Structure: secondary motor neuron Quality: mislocalised abnormal

Gene / Model

Organism

Observed Phenotype

atl1

Danio rerio

Structure: secondary motor neuron

Quality: mislocalised

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

endoplasmic reticulum organization
axonogenesis
protein homooligomerization
endoplasmic reticulum tubular network membrane organization

Molecular Function

GTPase activity
protein binding
GTP binding
identical protein binding

Cellular Component

Golgi cis cisterna
Golgi membrane
endoplasmic reticulum
endoplasmic reticulum membrane
Golgi apparatus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000358385
Coding exons: 14
Length: 100560
Individuals with no LoFs: 125738
Homozygous LoFs: 0
Heterozygous LoFs: 10
Defined: 125748
p: 0.0000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.63	168	295	0.569	0.0000147	3672
Missense (PolyPhen)		24	69.335	0.34614		906
Synonymous	0.0805	106	107	0.990	0.00000538	1023
Loss of Function	4.62	5	34.2	0.146	0.00000177	403

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000035	0.000035	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: GTPase tethering membranes through formation of trans- homooligomers and mediating homotypic fusion of endoplasmic reticulum membranes. Functions in endoplasmic reticulum tubular network biogenesis (PubMed:27619977). May also regulate Golgi biogenesis. May regulate axonal development. {ECO:0000269|PubMed:14506257, ECO:0000269|PubMed:17321752, ECO:0000269|PubMed:18270207, ECO:0000269|PubMed:19665976, ECO:0000269|PubMed:21220294, ECO:0000269|PubMed:23334294, ECO:0000269|PubMed:25751282, ECO:0000269|PubMed:27619977}.;
Disease: DISEASE: Neuropathy, hereditary sensory, 1D (HSN1D) [MIM:613708]: A disease characterized by adult-onset distal axonal sensory neuropathy leading to mutilating ulcerations as well as hyporeflexia. Some patients may show features suggesting upper neuron involvement. {ECO:0000269|PubMed:21194679}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.159

Intolerance Scores

LoFtool: 0.198
RVIS EVS: -0.58
RVIS percentile EVS: 18.44

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.453

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium