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Intellectual disability

Gene: TDP1

Amber List (moderate evidence)
TDP1 (tyrosyl-DNA phosphodiesterase 1)
EnsemblGeneIds (GRCh38): ENSG00000042088
EnsemblGeneIds (GRCh37): ENSG00000042088
OMIM: 607198, Gene2Phenotype
TDP1 is in 7 panels

10 reviews

Sarah Leigh (Genomics England Curator)

I don't know

Comment on list classification: This gene remains amber, as there are only two disease associated variants have been reported (PMID: 12244316;31182267;39576382).
Created: 3 Mar 2025, 5:20 p.m. | Last Modified: 3 Mar 2025, 5:20 p.m.
Panel Version: 8.118
Comment on publications: PMID: 39576382 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Created: 3 Mar 2025, 5:20 p.m. | Last Modified: 3 Mar 2025, 5:20 p.m.
Panel Version: 8.117
To date, two TDP1 variants have been associated with Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1, (OMIM:607250)(PMID: 12244316; 31182267; 39576382). One of the TDP1 variants (NM_001008744.1 c.1478A>G, p.His493Arg) has been identified in two Omani families and one Saudi Arabian Family. Haplotype analysis has confirmed that there is a single and mutually shared homozygous haplotype amongst probands of three families, therefore, this variant is a founder variant (PMID: 31182267). PMID: 39576382 reports the second TDP1 variant (NC_000014.9:g.89991982C>T; p.His478Tyr) in a case of OMIM:607250 in a consanguineous Pakistani family.
Created: 3 Mar 2025, 5:15 p.m. | Last Modified: 3 Mar 2025, 5:15 p.m.
Panel Version: 6.157

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
?Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1, OMIM:607250; spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1, MONDO:0011801

Publications

Created: 3 Mar 2025, 5:15 p.m.
Last Modified: 3 Mar 2025, 5:15 p.m.
Copied from panel: Hereditary neuropathy or pain disorder v6.158

Achchuthan Shanmugasundram (Genomics England Curator)

I don't know

Comment on list classification: This gene can now be promoted to AMBER as there are three unrelated cases. The "founder-effect" tag has been added as they are all of Middle Eastern descent and harboured the same homozygous variant. Hence, it cannot be promoted to green rating.
Created: 5 Apr 2023, 5:57 a.m. | Last Modified: 5 Apr 2023, 5:57 a.m.
Panel Version: 3.6
As reviewed by Ian Berry (Leeds Genetics Laboratory), there are now three unrelated families reported in literature with Spinocerebellar ataxia with axonal neuropathy-1 (SCAN1) and identified with homozygous variant in TDP1 gene. However, all three families are of Arab descent (one family from Saudi Arabia and two families from Oman) and they presented with the same homozygous variant (p.His493Arg).

There are a number of functional studies characterising the function of H493R variant in vitro (PMIDs:15920477, 17948061 & 31723605).

This gene has been associated with phenotypes in OMIM (MIM #607250), but not in Gene2Phenotype.
Created: 5 Apr 2023, 5:56 a.m. | Last Modified: 5 Apr 2023, 10:06 a.m.
Panel Version: 3.6

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
?Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1, OMIM:607250

Publications

Created: 5 Apr 2023, 5:56 a.m.
Last Modified: 5 Apr 2023, 10:06 a.m.
Copied from panel: Hereditary neuropathy or pain disorder v6.158

Ian Berry (Leeds Genetics Laboratory)

Green List (high evidence)

TDP1(NM_018319.4):c.1478A>G p.(His493Arg) has now been reported in 3 separate families with significant segregation data (homozygous/consanguineous Arabic cases, 10 affected individuals, >>>20 meioses).

We have seen one WGS case with presumed compound heteorzygosity (parents not tested) for this variant + a predicted likely LOF variant.

Reported phenotype is combination of cerebellar ataxia and axonal neuropathy, with gait disturbance.
Created: 27 Mar 2023, 12:37 p.m. | Last Modified: 27 Mar 2023, 12:37 p.m.
Panel Version: 3.2

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

Variants in this GENE are reported as part of current diagnostic practice

Created: 27 Mar 2023, 12:37 p.m.
Last Modified: 27 Mar 2023, 12:37 p.m.
Copied from panel: Hereditary neuropathy or pain disorder v6.158

Louise Daugherty (Genomics England Curator)

I don't know

Review and rating submitted by Natalie Forrester (SWGLH - Bristol Genetics) on behalf of South West GLH for GMS Neurology specialist test group.
Created: 29 Apr 2019, 12:53 p.m.
Created: 29 Apr 2019, 12:53 p.m.

Copied from panel: Hereditary neuropathy or pain disorder v6.158

Natalie Forrester (SWGLH - Bristol Genetics)

Red List (low evidence)

Bristol - no pathogenic or likely pathogenic variants out of approx.1900 patients tested. Not clearly associated with hereditary neuropathy. PMID: 12244316 - only report. Single family to date for the association with spinocerebellar ataxia
Created: 29 Apr 2019, 12:30 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Hereditary Neuropathies

Publications

Variants in this GENE are reported as part of current diagnostic practice

Created: 29 Apr 2019, 12:30 p.m.

Copied from panel: Hereditary neuropathy or pain disorder v6.158

Rita Horvath (Institute of Genetic Medicine, Newcastle University)

Green List (high evidence)

Created: 5 Nov 2017, 2:39 a.m.

Copied from panel: Hereditary neuropathy or pain disorder v6.158

Richard Scott (Genomics England Curator)

Comment on list classification: Single family reported to date
Created: 8 Jul 2016, 4:23 a.m.
Created: 8 Jul 2016, 4:23 a.m.

Copied from panel: Hereditary neuropathy or pain disorder v6.158

Ellen McDonagh (Genomics England Curator)

Comment on list classification: Seems to only have a single family to date for the association with spinocerebellar ataxia.
Created: 4 May 2016, 9:27 a.m.
Created: 4 May 2016, 9:27 a.m.

Copied from panel: Hereditary neuropathy or pain disorder v6.158

Alexander Rossor (UCL Institute of Neurology)

Spino cerebellar ataxia, single family
Created: 9 Dec 2015, 8:49 a.m.
Created: 9 Dec 2015, 8:49 a.m.

Copied from panel: Hereditary neuropathy or pain disorder v6.158

Mary Reilly (Institute of Neurology)

Spino cerebellar ataxia
Created: 8 Dec 2015, 3:05 p.m.
Created: 8 Dec 2015, 3:05 p.m.

Copied from panel: Hereditary neuropathy or pain disorder v6.158

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
  • NHS GMS
  • Expert list
  • Emory Genetics Laboratory
  • UKGTN
  • South West GLH
Phenotypes
  • ?Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1, OMIM:607250
Tags
founder-effect
OMIM
607198
Clinvar variants
Variants in TDP1
Penetrance
None
Publications
Panels with this gene

History Filter Activity

3 Mar 2025, Gel status: 2

Entity classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

Gene: tdp1 has been classified as Amber List (Moderate Evidence).

3 Mar 2025, Gel status: 2

Set publications

Sarah Leigh (Genomics England Curator)

Publications for gene: TDP1 were set to 12244316; 31182267; 39576382

3 Mar 2025, Gel status: 2

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

Sarah Leigh (Genomics England Curator)

gene: TDP1 was added gene: TDP1 was added to Intellectual disability. Sources: Expert Review Amber,South West GLH,UKGTN,Emory Genetics Laboratory,Expert list,NHS GMS founder-effect tags were added to gene: TDP1. Mode of inheritance for gene: TDP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TDP1 were set to 12244316; 31182267; 39576382 Phenotypes for gene: TDP1 were set to ?Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1, OMIM:607250