progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 5

Summary

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 5 (MONDO:0013117) is a disease caused by RRM2B (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: RRM2B (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 132

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 5
Mondo ID	MONDO:0013117
MeSH	C567768
OMIM	613077
DOID	DOID:0111518
UMLS	C2751319
MedGen	413981
GARD	0016501
Is cancer (heuristic)	no

Also known as: PEOA5 · progressive external ophthalmoplegia with mitochondrial DNA deletions caused by mutation in RRM2B · progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 5 · progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant type 5 · RRM2B progressive external ophthalmoplegia with mitochondrial DNA deletions

Data availability: 132 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › progressive external ophthalmoplegia › progressive external ophthalmoplegia with mitochondrial DNA deletions › autosomal dominant progressive external ophthalmoplegia › progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 5

Related subtypes (4): progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 2, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

132 retrieved; paginated sample, class counts are floors:

64 uncertain significance, 24 benign, 18 conflicting classifications of pathogenicity, 12 benign/likely benign, 4 pathogenic/likely pathogenic, 4 likely pathogenic, 4 pathogenic, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
132103	NM_015713.5(RRM2B):c.48G>A (p.Glu16=)	LOC130000896	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
132104	NM_015713.5(RRM2B):c.121C>T (p.Arg41Trp)	RRM2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
132122	NM_015713.5(RRM2B):c.671T>G (p.Ile224Ser)	RRM2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
215091	NM_015713.5(RRM2B):c.520C>T (p.Arg174Ter)	RRM2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2966802	NM_015713.5(RRM2B):c.158G>A (p.Trp53Ter)	RRM2B	Pathogenic	criteria provided, multiple submitters, no conflicts
30432	NM_015713.5(RRM2B):c.950del (p.Ser316_Leu317insTer)	RRM2B	Pathogenic	criteria provided, single submitter
30433	NM_015713.5(RRM2B):c.965dup (p.Asn322fs)	RRM2B	Pathogenic	no assertion criteria provided
5391	NM_015713.5(RRM2B):c.979C>T (p.Arg327Ter)	RRM2B	Pathogenic	criteria provided, multiple submitters, no conflicts
3595034	NM_015713.5(RRM2B):c.40C>T (p.Gln14Ter)	LOC130000896	Likely pathogenic	criteria provided, single submitter
132123	NM_015713.5(RRM2B):c.846G>C (p.Met282Ile)	RRM2B	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1524868	NM_015713.5(RRM2B):c.455+1G>A	RRM2B	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3595032	NM_015713.5(RRM2B):c.168T>A (p.Tyr56Ter)	RRM2B	Likely pathogenic	criteria provided, single submitter
1163492	NM_015713.5(RRM2B):c.119G>A (p.Arg40His)	RRM2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1256971	NM_015713.5(RRM2B):c.48+48C>T	RRM2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
132106	NM_015713.5(RRM2B):c.122G>C (p.Arg41Pro)	RRM2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
132109	NM_015713.5(RRM2B):c.253_255del (p.Glu85del)	RRM2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
132115	NM_015713.5(RRM2B):c.431C>T (p.Thr144Ile)	RRM2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
138933	NM_015713.5(RRM2B):c.48+96G>C	RRM2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
215088	NM_015713.5(RRM2B):c.544A>G (p.Thr182Ala)	RRM2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
215097	NM_015713.5(RRM2B):c.48+188del	RRM2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
361133	NM_015713.5(RRM2B):c.*3078G>T	RRM2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
361138	NM_015713.5(RRM2B):c.*2822A>T	RRM2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
361167	NM_015713.5(RRM2B):c.*817G>A	RRM2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
361175	NM_015713.5(RRM2B):c.*11G>A	RRM2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
361176	NM_015713.5(RRM2B):c.913G>T (p.Ala305Ser)	RRM2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
361177	NM_015713.5(RRM2B):c.790-9T>C	RRM2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
361178	NM_015713.5(RRM2B):c.756G>A (p.Arg252=)	RRM2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
361179	NM_015713.5(RRM2B):c.540A>G (p.Lys180=)	RRM2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
624342	NM_015713.5(RRM2B):c.790-2A>G	RRM2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
909125	NM_015713.4(RRM2B):c.-101G>A	RRM2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
RRM2B	Definitive	Autosomal recessive	mitochondrial DNA depletion syndrome 8a	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RRM2B	Orphanet:254892	Autosomal dominant progressive external ophthalmoplegia
RRM2B	Orphanet:255235	Mitochondrial DNA depletion syndrome, encephalomyopathic form with renal tubulopathy
RRM2B	Orphanet:298	Mitochondrial neurogastrointestinal encephalomyopathy
RRM2B	Orphanet:329336	Adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy
RRM2B	Orphanet:480	Kearns-Sayre syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RRM2B	HGNC:17296	ENSG00000048392	Q7LG56	Ribonucleoside-diphosphate reductase subunit M2 B	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RRM2B	Ribonucleoside-diphosphate reductase subunit M2 B	Plays a pivotal role in cell survival by repairing damaged DNA in a p53/TP53-dependent manner.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RRM2B	Enzyme (other)	yes	1.17.4.1	RNR_small_fam, Ferritin-like_SF, RNR-like

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
deltoid	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RRM2B	254	ubiquitous	marker	secondary oocyte, oocyte, deltoid

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RRM2B	2,432

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RRM2B	Q7LG56	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interconversion of nucleotide di- and triphosphates	1	356.9×	0.006	RRM2B
TP53 Regulates Metabolic Genes	1	129.8×	0.008	RRM2B

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
deoxyribonucleoside triphosphate metabolic process	1	16852.0×	6e-04	RRM2B
ribonucleoside diphosphate metabolic process	1	5617.3×	6e-04	RRM2B
deoxyribonucleotide biosynthetic process	1	5617.3×	6e-04	RRM2B
2’-deoxyribonucleotide biosynthetic process	1	5617.3×	6e-04	RRM2B
positive regulation of G0 to G1 transition	1	3370.4×	8e-04	RRM2B
negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator	1	2407.4×	1e-03	RRM2B
response to amine	1	1872.4×	0.001	RRM2B
mitochondrial DNA replication	1	1532.0×	0.001	RRM2B
renal system process	1	1123.5×	0.001	RRM2B
DNA synthesis involved in DNA repair	1	936.2×	0.001	RRM2B
positive regulation of G2/M transition of mitotic cell cycle	1	601.9×	0.002	RRM2B
kidney development	1	140.4×	0.008	RRM2B
response to oxidative stress	1	130.6×	0.008	RRM2B
DNA repair	1	63.8×	0.016	RRM2B

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RRM2B	1	3

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TRIAPINE	3	RRM2B

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
RRM2B	47	Binding:44, Functional:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RRM2B	1.17.4.1	ribonucleoside-diphosphate reductase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
TRIAPINE	3	RRM2B

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	RRM2B
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.