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Genetic epilepsy syndromes

Gene: RRM2B

Amber List (moderate evidence)

RRM2B (ribonucleotide reductase regulatory TP53 inducible subunit M2B)
EnsemblGeneIds (GRCh38): ENSG00000048392
EnsemblGeneIds (GRCh37): ENSG00000048392
OMIM: 604712, Gene2Phenotype
RRM2B is in 21 panels

3 reviews

Tracy Lester (Genetics laboratory, Oxford UK)

Green List (high evidence)

Mitochondrial disorders can associated with seizures, but the evidence is not specifically implicated. There are reports of disease-causing variants being associated with mitochondrial DNA depletion syndrome.
Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.
Panel Version: 1.188

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy), 612075; Mitochondrial DNA depletion syndrome 8B (MNGIE type), 612075; Progressive external ophthalmoplegia with mitochondrial DNA deletions 5, 613077

Publications

Rebecca Foulger (Genomics England curator)

I don't know

As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Better tested through the metabolic panel. Kept rating as Amber.
Created: 25 Nov 2019, 8:43 p.m. | Last Modified: 25 Nov 2019, 8:43 p.m.
Panel Version: 1.436
As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that this gene can remain as Amber: RRM2B is Green on the 'Inborn errors of metabolism' panel (467) so will be Green on the Epilepsy Super panel (489).
Created: 15 Aug 2019, 8:09 a.m. | Last Modified: 15 Aug 2019, 8:09 a.m.
Panel Version: 1.223
Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: Alison Callaway and John Taylor. Suggested gene rating: Green.
Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.
Panel Version: 1.189
Comment on list classification: Kept rating as Amber after reviewing the literature evidence. The main phenotype manifests as hypotonia with lactic acidosis. Although seizures have been reported, they are variable and not common (PMID:29241262 summary records seizures in 6/78 patients, PMID:18504129 don't report seizures in any of their three patients).
Created: 24 Jun 2019, 1:07 p.m. | Last Modified: 24 Jun 2019, 1:07 p.m.
Panel Version: 1.71
Bourdon et al., 2007 (PMID:17486094) studied 7 cases of mitochondrial depletion in 4 unrelated families with RRM2B variants. Seizures were reported in Family 2: Subject 4 showed trunk hypotonia and tubulopathy shortly after birth. At 20 days of life he developed seizures, and died at 2 months after status epilepticus. His sister (Subject 5) had a similar clinical course (the authors don't explicitly state whether she had seizures).
Created: 24 Jun 2019, 12:57 p.m. | Last Modified: 24 Jun 2019, 12:57 p.m.
Panel Version: 1.68
Bornstein et al., 2008 (PMID:18504129) sequenced the RRM2B gene in 3 unrelated cases- The common clinical feature was myopathy with lactic acidosis, and none had overt seizures.
Created: 24 Jun 2019, 12:41 p.m. | Last Modified: 24 Jun 2019, 12:41 p.m.
Panel Version: 1.66
PMID:19138848 (Kollberg et al., 2009) report two Sudanese brothers with a severe form of fatal autosomal recessive encephalomyopathic mtDNA depletion syndrome-8B caused by a homozygous mutation in the RRM2B gene. Both brothers had seizures amongst their phenotypes.
Created: 24 Jun 2019, 12:41 p.m. | Last Modified: 24 Jun 2019, 12:43 p.m.
Panel Version: 1.68
PMID:28482374 (Kropach et al) report 2 siblings with a variant in RRM2B and early fatal encephalomyopathy. At least the older brother had focal seizures. As pointed out in http://www.currentneurobiology.org/neurobiology/phenotypic-heterogeneity-of-rrm2b-mutations.pdf, limited information is provided about the patients and the variant.
Created: 24 Jun 2019, 11:05 a.m. | Last Modified: 24 Jun 2019, 11:05 a.m.
Panel Version: 1.64

Zornitza Stark (Australian Genomics)

Seizures are part of the phenotype of this mitochondrial disorder.
Created: 20 Aug 2018, 12:44 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy), MIM#612075

Publications

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

History Filter Activity

15 Aug 2019, Gel status: 2

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: rrm2b has been classified as Amber List (Moderate Evidence).

6 Aug 2019, Gel status: 2

Added New Source

Rebecca Foulger (Genomics England curator)

Source Wessex and West Midlands GLH was added to RRM2B.

6 Aug 2019, Gel status: 2

Added New Source

Rebecca Foulger (Genomics England curator)

Source NHS GMS was added to RRM2B.

24 Jun 2019, Gel status: 2

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: rrm2b has been classified as Amber List (Moderate Evidence).

24 Jun 2019, Gel status: 2

Set publications

Rebecca Foulger (Genomics England curator)

Publications for gene: RRM2B were set to

24 Jun 2019, Gel status: 2

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for gene: RRM2B were changed from Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy), 612075; seizures to Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy), 612075; seizures; status epilepticus

24 Jun 2019, Gel status: 2

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for gene: RRM2B were changed from to Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy), 612075; seizures

24 Jun 2019, Gel status: 2

Set mode of inheritance

Rebecca Foulger (Genomics England curator)

Mode of inheritance for gene: RRM2B was changed from to BIALLELIC, autosomal or pseudoautosomal

11 Dec 2018, Gel status: 2

Panel promoted to version 1.0

Sarah Leigh (Genomics England Curator)

Zornitza Stark: Seizures are part of the pheno

25 Jun 2018, Gel status: 2

Added New Source

Sarah Leigh (Genomics England Curator)

Expert Review Amber was added to RRM2B. Panel: Genetic Epilepsy Syndromes

25 Jun 2018, Gel status: 1

Added New Source

Sarah Leigh (Genomics England Curator)

RRM2B was added to Genetic Epilepsy Syndromes panel. Sources: Victorian Clinical Genetics Services

25 Jun 2018, Gel status: 1

Created

Sarah Leigh (Genomics England Curator)

RRM2B was created by Sarah Leigh