progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3

Summary

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3 (MONDO:0014898) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 26

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 recessive 3
Mondo ID	MONDO:0014898
OMIM	617069
DOID	DOID:0111523
UMLS	C4310734
MedGen	934701
GARD	0016183
Is cancer (heuristic)	no

Also known as: autosomal recessive progressive external ophthalmoplegia caused by mutation in TK2 · PEOB3 · progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3 · progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3; PEOB3 · progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive type 3 · TK2 autosomal recessive progressive external ophthalmoplegia

Data availability: 26 ClinVar variants.

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 › progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3

Related subtypes (7): autosomal dominant progressive external ophthalmoplegia, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1, mitochondrial DNA deletion syndrome with progressive myopathy, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 5, progressive external ophthalmoplegia with mitochondrial dna deletions, autosomal recessive 6

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

26 retrieved; paginated sample, class counts are floors:

7 pathogenic/likely pathogenic, 7 pathogenic, 5 conflicting classifications of pathogenicity, 3 benign, 3 likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1190844	NM_004614.5(TK2):c.623A>G (p.Tyr208Cys)	TK2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12710	NM_004614.5(TK2):c.323C>T (p.Thr108Met)	TK2	Pathogenic	criteria provided, multiple submitters, no conflicts
1323691	NM_004614.5(TK2):c.441del (p.Tyr148fs)	TK2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1410181	NM_004614.5(TK2):c.415G>A (p.Ala139Thr)	TK2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1496034	NM_004614.5(TK2):c.1A>T (p.Met1Leu)	TK2	Pathogenic	criteria provided, multiple submitters, no conflicts
265614	NM_004614.5(TK2):c.372_373delinsCT (p.Gln125Ter)	TK2	Pathogenic	criteria provided, multiple submitters, no conflicts
3581130	NM_004614.5(TK2):c.544del (p.Leu182fs)	TK2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
38974	NM_004614.5(TK2):c.133C>T (p.Gln45Ter)	TK2	Pathogenic	criteria provided, multiple submitters, no conflicts
38978	NM_004614.5(TK2):c.173A>G (p.Asn58Ser)	TK2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
38979	NM_004614.5(TK2):c.191C>T (p.Thr64Met)	TK2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
38986	NM_004614.5(TK2):c.360_361delinsAA (p.His121Asn)	TK2	Pathogenic	criteria provided, multiple submitters, no conflicts
38990	NM_004614.5(TK2):c.416C>T (p.Ala139Val)	TK2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
38992	NM_004614.5(TK2):c.547C>T (p.Arg183Trp)	TK2	Pathogenic	criteria provided, multiple submitters, no conflicts
972912	NM_004614.5(TK2):c.144_145del (p.Lys50fs)	TK2	Pathogenic	criteria provided, multiple submitters, no conflicts
3897043	NM_004614.5(TK2):c.643C>A (p.Leu215Ile)	TK2	Likely pathogenic	criteria provided, single submitter
38993	NM_004614.5(TK2):c.562A>G (p.Thr188Ala)	TK2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4849482	NM_004614.5(TK2):c.622T>C (p.Tyr208His)	TK2	Likely pathogenic	criteria provided, single submitter
1217245	NM_004614.5(TK2):c.588A>T (p.Arg196Ser)	TK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1643070	NM_004614.5(TK2):c.367C>G (p.Arg123Gly)	TK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2628100	NM_004614.5(TK2):c.126_128del (p.Asp42_Lys43delinsGlu)	TK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3897062	NM_004614.5(TK2):c.331A>G (p.Thr111Ala)	TK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
972913	NM_004614.5(TK2):c.659T>C (p.Leu220Pro)	TK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
137665	NM_004614.5(TK2):c.-38A>G	TK2	Benign	criteria provided, multiple submitters, no conflicts
137666	NM_004614.5(TK2):c.-30C>G	TK2	Benign	criteria provided, multiple submitters, no conflicts
137668	NM_004614.5(TK2):c.231+10C>T	TK2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
673678	NM_004614.5(TK2):c.619-53A>G	TK2	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TK2	Orphanet:254875	Mitochondrial DNA depletion syndrome, myopathic form
TK2	Orphanet:254886	Autosomal recessive progressive external ophthalmoplegia

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
TK2	HGNC:11831	ENSG00000166548	O00142	Thymidine kinase 2, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TK2	Thymidine kinase 2, mitochondrial	Phosphorylates thymidine, deoxycytidine, and deoxyuridine in the mitochondrial matrix.

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TK2	Kinase	yes	2.7.1.21	DCK/DGK, P-loop_NTPase, DNK_dom

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
adrenal tissue	1
calcaneal tendon	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TK2	280	ubiquitous	marker	calcaneal tendon, sural nerve, adrenal tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TK2	2,031

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TK2	O00142	85.01

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Nucleotide salvage	1	1142.0×	0.002	TK2
Pyrimidine salvage	1	1038.2×	0.002	TK2
Metabolism of nucleotides	1	300.5×	0.004	TK2
Metabolism	1	11.6×	0.086	TK2

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
deoxycytidine metabolic process	1	16852.0×	2e-04	TK2
pyrimidine nucleoside salvage	1	8426.0×	2e-04	TK2
thymidine metabolic process	1	8426.0×	2e-04	TK2
DNA biosynthetic process	1	802.5×	0.002	TK2
nucleobase-containing compound metabolic process	1	526.6×	0.002	TK2

Therapeutics

Drug target analysis

Approved (phase 4): 1 · 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).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
TK2	SORIVUDINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TK2	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SORIVUDINE	4	TK2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
TK2	17	Binding:17

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TK2	2.7.1.21	thymidine kinase

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)
SORIVUDINE	4	TK2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TK2
B	Phased (≥1) drug, not yet approved	0
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.