Optic atrophy 5

Summary

Optic atrophy 5 (MONDO:0012543) is a disease caused by DNM1L (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: DNM1L (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 17

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	optic atrophy 5
Mondo ID	MONDO:0012543
MeSH	C537126
OMIM	610708
DOID	DOID:0111438
UMLS	C1853139
MedGen	377837
GARD	0010201
Is cancer (heuristic)	no

Also known as: OPA5 · optic atrophy 5

Data availability: 17 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › autosomal dominant optic atrophy › optic atrophy 5

Related subtypes (5): optic atrophy 3, autosomal dominant optic atrophy, classic form, autosomal dominant optic atrophy plus syndrome, autosomal dominant optic atrophy and peripheral neuropathy, Al Gazali Khidr Prem Chandran syndrome

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

17 retrieved; paginated sample, class counts are floors:

5 pathogenic, 4 benign/likely benign, 4 benign, 2 uncertain significance, 1 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
214313	NM_012062.5(DNM1L):c.1207C>T (p.Arg403Cys)	DNM1L	Pathogenic	criteria provided, multiple submitters, no conflicts
420713	NM_012062.5(DNM1L):c.1292G>A (p.Cys431Tyr)	DNM1L	Pathogenic	criteria provided, multiple submitters, no conflicts
446169	NM_012062.5(DNM1L):c.5A>C (p.Glu2Ala)	DNM1L	Pathogenic	no assertion criteria provided
446170	NM_012062.5(DNM1L):c.575C>A (p.Ala192Glu)	DNM1L	Pathogenic	no assertion criteria provided
619028	NM_012062.5(DNM1L):c.2072A>G (p.Tyr691Cys)	DNM1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
689730	NM_012062.5(DNM1L):c.763_764dup (p.Lys256fs)	DNM1L	Pathogenic	criteria provided, single submitter
1503004	NM_012062.5(DNM1L):c.1596+2T>A	DNM1L	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1683649	NM_012062.5(DNM1L):c.1289G>A (p.Arg430His)	DNM1L	Uncertain significance	criteria provided, single submitter
214308	NM_012062.5(DNM1L):c.305C>T (p.Thr102Met)	DNM1L	Uncertain significance	criteria provided, multiple submitters, no conflicts
214301	NM_012062.5(DNM1L):c.741-19G>A	DNM1L	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
214306	NM_012062.5(DNM1L):c.1885-15del	DNM1L	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
260165	NM_012062.5(DNM1L):c.120A>C (p.Ser40=)	DNM1L	Benign	criteria provided, multiple submitters, no conflicts
260167	NM_012062.5(DNM1L):c.252G>A (p.Gly84=)	DNM1L	Benign	criteria provided, multiple submitters, no conflicts
260168	NM_012062.5(DNM1L):c.918A>G (p.Thr306=)	DNM1L	Benign	criteria provided, multiple submitters, no conflicts
308394	NM_012062.5(DNM1L):c.*21G>C	DNM1L	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
308396	NM_012062.5(DNM1L):c.*22A>T	DNM1L	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
671645	NM_012062.5(DNM1L):c.1674+36T>A	DNM1L	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 2 · 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
DNM1L	Strong	Autosomal dominant	optic atrophy 5	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DNM1L	Orphanet:330050	DNM1L-related encephalopathy due to mitochondrial and peroxisomal fission defect
DNM1L	Orphanet:98673	Autosomal dominant optic atrophy, classic form

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
DNM1L	HGNC:2973	ENSG00000087470	O00429	Dynamin-1-like protein	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DNM1L	Dynamin-1-like protein	Functions in mitochondrial and peroxisomal division.

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)
DNM1L	Enzyme (other)	yes	3.6.5.5	Dynamin_stalk, Dynamin_GTPase, GED

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
lateral nuclear group of thalamus	1
sperm	1
substantia nigra pars compacta	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DNM1L	295	ubiquitous	marker	lateral nuclear group of thalamus, substantia nigra pars compacta, sperm

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DNM1L	4,801

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DNM1L	O00429	11

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Apoptotic execution phase	1	475.8×	0.002	DNM1L

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
mitochondrial membrane fission	1	8426.0×	0.001	DNM1L
regulation of ATP metabolic process	1	8426.0×	0.001	DNM1L
regulation of peroxisome organization	1	5617.3×	0.001	DNM1L
mitocytosis	1	2808.7×	0.002	DNM1L
intracellular distribution of mitochondria	1	2407.4×	0.002	DNM1L
peroxisome fission	1	1532.0×	0.002	DNM1L
mitochondrial fragmentation involved in apoptotic process	1	1404.3×	0.002	DNM1L
protein localization to mitochondrion	1	1296.3×	0.002	DNM1L
regulation of mitophagy	1	1203.7×	0.002	DNM1L
mitochondrial fission	1	1053.2×	0.002	DNM1L
heart contraction	1	766.0×	0.002	DNM1L
positive regulation of mitochondrial fission	1	766.0×	0.002	DNM1L
protein complex oligomerization	1	674.1×	0.002	DNM1L
positive regulation of neutrophil chemotaxis	1	648.1×	0.002	DNM1L
positive regulation of protein secretion	1	343.9×	0.004	DNM1L
rhythmic process	1	251.5×	0.005	DNM1L
calcium ion transport	1	181.2×	0.006	DNM1L
mitochondrion organization	1	151.8×	0.007	DNM1L
endocytosis	1	95.2×	0.011	DNM1L
regulation of gene expression	1	83.4×	0.012	DNM1L

Therapeutics

Drug target analysis

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

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
DNM1L	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
DNM1L	4	Binding:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DNM1L	3.6.5.5	dynamin GTPase

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

0 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.

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	0
C	Druggable family + PDB, no drug	1	DNM1L
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DNM1L	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.