Hereditary neuropathy or pain disorder

Gene: TDP1

Green List (high evidence)

Further Sheffield case identified in the WGS cohort with the common variant p.(His493Arg) and a likely LoF splicing variant. Our patient had early adulthood onset progressive ataxia and axonal neuropathy.

Alongside the papers and cases discussed lower down this page, enough cases for this gene to be promoted to green on the R78 neuropathy panel. Already green on the R54 adulthood onset ataxia panel.

Created: 19 Sep 2025, 2:55 p.m. | Last Modified: 19 Sep 2025, 2:55 p.m.

Panel Version: 7.8

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Spinocerebellar ataxia with axonal neuropathy (OMIM: 607250)

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

I don't know

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, 5:19 p.m. | Last Modified: 3 Mar 2025, 5:19 p.m.

Panel Version: 6.161

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, 5:18 p.m. | Last Modified: 3 Mar 2025, 5:18 p.m.

Panel Version: 6.160

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

• 39576382

Green List (high evidence)

Comment on list classification: There are at least three different variants reported (two published variants including the founder-variant from the Middle East) in five unrelated families including the Sheffield case. There is also sufficient functional evidence available in support of the p.His493Arg founder variant. Hence, this gene can be promoted to green rating in the next GMS update.

Created: 24 Oct 2025, 1:28 p.m. | Last Modified: 24 Oct 2025, 1:28 p.m.

Panel Version: 7.23

Comment on phenotypes: OMIM accessed 24 October 2025.

Created: 24 Oct 2025, 1:25 p.m. | Last Modified: 24 Oct 2025, 1:25 p.m.

Panel Version: 7.22

As reviewed before, PMID:31182267 reported three unrelated probands (two Omani families and one Saudi Arabian family) with homozygous missense variant in TDP1 gene - p.His493Arg, which has been confirmed by haplotype analysis as a founder variant. However, the allele count for this variant in gnomAD v4.1.0 is 13 and it is not found in homozygous state in any of those individuals. In addition, there is also functional evidence available that showed that cells expressing TDP1 gene with H493R variant promotes mitochondrial dysfunction and mitophagy.

PMID:39576382 reported a female patient from a Pakistani family with autosomal recessive spinocerebellar ataxia with axonal neuropathy type 1, who presented with additional clinical features including congenital onset of disease. This patient was identified with a novel missense variant in TDP1 (p.His478Tyr) via WES, and autosomal recessive segregation was confirmed by Sanger sequencing. The allele count for this variant in gnomAD v4.1.0 is 10, of which eight were from South Asian ancestry - however, it is absent in homozygous state in the database.

As reviewed by Ian Berry and Lauren Turton, there is an additional case reported in with p.His493Arg variant and a likely LoF splicing variant, who had early adulthood onset progressive ataxia and axonal neuropathy.

Created: 10 Oct 2025, 10:38 a.m. | Last Modified: 24 Oct 2025, 1:22 p.m.

Panel Version: 7.21

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; spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1, MONDO:0011801

Publications

• 12244316
• 15920477
• 17948061
• 31182267
• 31723605
• 39576382

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

• PMID: 12244316
• PMID: 31182267

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

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.

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

• 12244316

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

Green List (high evidence)

Comment on list classification: Single family reported to date

Created: 8 Jul 2016, 4:23 a.m.

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.

Spino cerebellar ataxia, single family

Created: 9 Dec 2015, 8:49 a.m.

Spino cerebellar ataxia

Created: 8 Dec 2015, 3:05 p.m.