Hereditary neuropathy or pain disorder

Gene: ATL3

Green List (high evidence)

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

Created: 24 Feb 2025, 5:02 p.m. | Last Modified: 24 Feb 2025, 5:02 p.m.

Panel Version: 6.148

Two ATL3 variants have been associated with Neuropathy, hereditary sensory, type IF (OMIM:615632). Rs587777108 has been found in a four generation family with OMIM:615632 from Germany. The affected members of a Spanish family also carried this variant. Haplotype analysis suggested a founder effect for this variant (PMID: 24459106). In vitro functional expression studies revealed that rs587777108 in COS-7 cells, revealed that the variant peptide was mislocated, resulting in its accumulation in condensed structures close to the nucleus, overall, this resulted in a dominant-negative disruption of the endoplasmic reticulum (PMID: 24459106). A further variant (rs1939486740) was reported in two unrelated families. Segregation of the variant and OMIM:615632 was recorded in both cases and in vitro studies in HeLa cells also revealed disruption to localization and suggested a dominant-negative effect (PMID: 24736309; 30680846).

Created: 4 Nov 2024, 11:26 a.m. | Last Modified: 4 Nov 2024, 11:26 a.m.

Panel Version: 6.20

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Neuropathy, hereditary sensory, type IF, OMIM:615632; neuropathy, hereditary sensory, type 1F, MONDO:0014286

Publications

• 24736309
• 24459106
• 30680846

Green List (high evidence)

3rd indivudla reported with domintant ATL3 and neuropathy

Created: 15 Oct 2024, 10:26 p.m. | Last Modified: 15 Oct 2024, 10:26 p.m.

Panel Version: 5.19

Autosomal dominant HSN, several families described . Previous recessive entry was an error

Created: 16 May 2019, 12:02 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Publications

• 30680846

I don't know

Literature search 6th May 2016, 2 articles found PMID: 24459106 c.575A>G (p.Tyr192Cys) heterozygous segregated with affected family members in a German family and Spanish family with hereditary sensory and autonomic neuropathies type 1, Haplotype analysis at the ATL3 locus of both families suggested that they share the same alleles compatible with identity by descent; PMID:24736309 - report of a Bosnian family, in which father and son with hereditary sensory neuropathy type 1 were heterozygous for ATL3 c.1013C>G p.Pro338Arg, that was not found in unaffected son

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

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Publications

• 24459106
• 24736309

I don't know

Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Re-evaluation of evidence - demotion / Limited evidence highlighted by Natalie - same variant in 2 families and other variant didn't segregate - downgrade to Amber? Agree downgrade due to lack of evidence

Created: 6 Dec 2019, 2:16 p.m. | Last Modified: 6 Dec 2019, 2:16 p.m.

Panel Version: 0.35

Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.

Created: 6 Dec 2019, 1:17 p.m. | Last Modified: 6 Dec 2019, 1:17 p.m.

Panel Version: 0.8

Rating and review submitted on behalf of James Polke (Neurogenetics Laboratory,Institute of Neurology, London), on behalf of London North GLH for GMS Neurology specialist test group.

Created: 9 May 2019, 5 p.m.

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.

Green List (high evidence)

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Comment when marking as ready: 24459106 and 24736309 both demonstrate monoallelic (AD) inheritance

Created: 8 Jul 2016, 3:22 a.m.

Comment on mode of inheritance: The literature reports and OMIM state monoallelic inheritance (variants found in a heterozygous state), but both reviewers suggested biallelic.

Created: 6 May 2016, 8:26 a.m.

Comment on list classification: A reviewer added the gene, and a second reviewer rated this green.

Created: 6 May 2016, 8:24 a.m.