Hereditary neuropathy or pain disorder

Gene: POLR3A

Green List (high evidence)

Comment on mode of inheritance: As reviewed by Alexander Rossor, there are 8 unrelated families reported with monoallelic variants and early-onset peripheral neuropathy. Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.

Created: 27 Jul 2026, 9:29 a.m. | Last Modified: 27 Jul 2026, 9:29 a.m.

Panel Version: 8.17

PMID:42260910 (2026) reported 11 patients from 8 unrelated families identified with heterozygous missense variants in POLR3A. The patients presented with an early-onset, progressive sensorimotor peripheral polyneuropathy with intermediate to demyelinating ranges of nerve conduction slowing, occasionally accompanied with neurological or non-neurological features. White matter abnormalities that are characteristic for the biallelic Pol III-related disorders were not observed in the brain magnetic resonance imaging.

Although biallelic variants in this gene has already been associated with phenotypes relevant for this panel on OMIM (MIM #607694, last accessed 26 July 2026) and ClinGen (with 'definitive; rating by Leukodystrophy and Leukoencephalopathy GCEP), monoallelic variants are not yet associated with relevant phenotypes in these resources.

Created: 27 Jul 2026, 9:19 a.m. | Last Modified: 27 Jul 2026, 9:19 a.m.

Panel Version: 8.12

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

Created: 26 Sep 2024, 1:11 p.m. | Last Modified: 26 Sep 2024, 1:11 p.m.

Panel Version: 5.16

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, OMIM:607694; leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, MONDO:0011897; peripheral neuropathy, MONDO:0005244

Publications

• 42260910

Green List (high evidence)

Numerous POLR3A variants have been associated with OMIM:607694 and OMIM:264090. This gene should be green on this panel, as the panel scope now includes complex phenotypes.

Created: 13 May 2024, 8:57 a.m. | Last Modified: 13 May 2024, 8:57 a.m.

Panel Version: 4.11

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Wiedemann-Rautenstrauch syndrome, OMIM:264090; Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism OMIM:607694

I don't know

Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart): Extension of panel scope - ataxia with neuropathy / Broader phenotype: spastic ataxia with abnormal nerve conduction in 8/14 cases

Created: 7 Dec 2019, 12:03 a.m. | Last Modified: 7 Dec 2019, 12:03 a.m.

Panel Version: 0.86

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, 10:25 p.m. | Last Modified: 6 Dec 2019, 10:25 p.m.

Panel Version: 0.84

Review and rating uploaded from file (Curation_Template_GMS_Neuro_AR_20190521.xlsx) submitted by Alex Rossor (UCL Institute of Neurology) on behalf of London North GLH for GMS Neurology specialist test group.

Created: 11 Jun 2019, 1:40 p.m.

Green List (high evidence)

8 unrelated patients. Should also add monoalleleic POLR3A variants to the panel (not just bialleleic)

Created: 12 Jul 2026, 11:46 a.m. | Last Modified: 12 Jul 2026, 11:46 a.m.

Panel Version: 8.9

should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46

Created: 17 Mar 2024, 9:31 p.m. | Last Modified: 17 Mar 2024, 9:31 p.m.

Panel Version: 3.83

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Early onset peripheral neuropathy

Publications

• 42260910