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Hereditary Spastic Paraplegia - paediatric

Gene: ATL1

Green List (high evidence)
ATL1 (atlastin GTPase 1)
EnsemblGeneIds (GRCh38): ENSG00000198513
EnsemblGeneIds (GRCh37): ENSG00000198513
OMIM: 606439, Gene2Phenotype
ATL1 is in 8 panels

3 reviews

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Green List (high evidence)

No clear genotype-phenotype correlation. However, most SPG3A exhibits an early onset, and most mutations are missense mutations (PMID: 28396731). Hom nonsense (PMID: 24473461) and hom missense (PMID: 26888483) were reported for AR HSP. Disease mechanism (PTC variants): LoF LoF: hom nonsense (p.R217* in alt transcript) identified in a consanguineous family, and carriers are healthy (PMID: 26888483). Disease mechanism (missense variants): Dominant negative: Mutant atlastin-1 protein functionally impair the atlastin-1 oligomer by binding to WT protein —> reduce GTPase activity (PMID: 16537571) —> cause HSP3A LoF: Variants fall outside of the GTPase related motifs or the conserved motifs is linked to neuropathy, suggesting an alternative mechanism is used apart from dom-neg (PMID: 28396731) —> cause HSN1D More than 90% of the mutations were located in exon 4, 7, 8 and 12 (PMID: 16401858)
Created: 11 May 2020, 11:12 a.m. | Last Modified: 11 May 2020, 11:12 a.m.
Panel Version: 0.84

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Hereditary sensory neuropathy type ID, MIM 613708; Spastic paraplegia 3A, MIM 182600; Hereditary spastic paraplegia, AR

Publications

Created: 11 May 2020, 11:12 a.m.
Last Modified: 11 May 2020, 11:12 a.m.
Panel version: 0.84

Teresa Zhao (Victorian Clinical Genetics Services)

Green List (high evidence)

No clear genotype-phenotype correlation. However, most SPG3A exhibits an early onset, and most mutations are missense mutations (PMID: 28396731).
Hom nonsense (PMID: 24473461) and hom missense (PMID: 26888483) were reported for AR HSP.

Disease mechanism (PTC variants): LoF
LoF: hom nonsense (p.R217* in alt transcript) identified in a consanguineous family, and carriers are healthy (PMID: 26888483).

Disease mechanism (missense variants): 
Dominant negative: Mutant atlastin-1 protein functionally impair the atlastin-1 oligomer by binding to WT protein —> reduce GTPase activity (PMID: 16537571) —> cause HSP3A
LoF: Variants fall outside of the GTPase related motifs or the conserved motifs is linked to neuropathy, suggesting an alternative mechanism is used apart from dom-neg (PMID: 28396731) —> cause HSN1D

More than 90% of the mutations were located in exon 4, 7, 8 and 12 (PMID: 16401858)
Created: 11 May 2020, 10:27 a.m. | Last Modified: 11 May 2020, 10:27 a.m.
Panel Version: 0.20

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Hereditary sensory neuropathy type ID, MIM 613708; Spastic paraplegia 3A, MIM 182600; Hereditary spastic paraplegia, AR

Publications

Mode of pathogenicity
Other

Created: 11 May 2020, 10:27 a.m.
Last Modified: 11 May 2020, 10:27 a.m.
Panel version: Imported from Hereditary Spastic Paraplegia panel version 0.20

Bryony Thompson (Royal Melbourne Hospital)

Green List (high evidence)

Usually shows early age at onset.
Sources: Expert list
Created: 17 Apr 2020, 6:50 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Spastic paraplegia 3A, autosomal dominant MIM#182600

Created: 17 Apr 2020, 6:50 a.m.

Panel version: 0.8

Details

Mode of Inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Expert list
Phenotypes
  • Hereditary sensory neuropathy type ID, MIM 613708
  • Spastic paraplegia 3A, MIM 182600
  • Hereditary spastic paraplegia, AR
OMIM
606439
Clinvar variants
Variants in ATL1
Penetrance
None
Publications
Panels with this gene

History Filter Activity

11 May 2020, Gel status: 3

Set Phenotypes

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Phenotypes for gene: ATL1 were changed from Spastic paraplegia 3A, autosomal dominant MIM#182600 to Hereditary sensory neuropathy type ID, MIM 613708; Spastic paraplegia 3A, MIM 182600; Hereditary spastic paraplegia, AR

11 May 2020, Gel status: 3

Set publications

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Publications for gene: ATL1 were set to

11 May 2020, Gel status: 3

Set mode of inheritance

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Mode of inheritance for gene: ATL1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal

17 Apr 2020, Gel status: 3

Entity classified by Genomics England curator

Bryony Thompson (Royal Melbourne Hospital)

Gene: atl1 has been classified as Green List (High Evidence).

17 Apr 2020, Gel status: 3

Entity classified by Genomics England curator

Bryony Thompson (Royal Melbourne Hospital)

Gene: atl1 has been classified as Green List (High Evidence).

17 Apr 2020, Gel status: 1

Created, Added New Source, Set mode of inheritance, Set Phenotypes

Bryony Thompson (Royal Melbourne Hospital)

gene: ATL1 was added gene: ATL1 was added to Hereditary Spastic Paraplegia - paediatric. Sources: Expert list Mode of inheritance for gene: ATL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: ATL1 were set to Spastic paraplegia 3A, autosomal dominant MIM#182600 Review for gene: ATL1 was set to GREEN