autosomal recessive optic atrophy, OPA7 type

Summary

autosomal recessive optic atrophy, OPA7 type (MONDO:0013069) is a disease caused by TMEM126A (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TMEM126A (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 22

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		17	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive optic atrophy, OPA7 type
Mondo ID	MONDO:0013069
MeSH	C567833
OMIM	612989
Orphanet	227976
DOID	DOID:0111437
UMLS	C2751812
MedGen	414112
GARD	0017143
Is cancer (heuristic)	no

Also known as: OPA7 · optic atrophy 7 with or without auditory neuropathy · TMEM126A-related optic atrophy with or without extraocular features

Data availability: 22 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › mitochondrial oxidative phosphorylation disorder › autosomal recessive optic atrophy, OPA7 type

Related subtypes (47): mitochondrial respiratory chain complex deficiency, combined oxidative phosphorylation deficiency, myopathy, lactic acidosis, and sideroblastic anemia, optic atrophy 3, autosomal dominant optic atrophy, classic form, Leigh syndrome, mitochondrial non-syndromic sensorineural hearing loss, maternally-inherited diabetes and deafness, chronic diarrhea with villous atrophy, Kearns-Sayre syndrome, Leber hereditary optic neuropathy, NARP syndrome, deafness, aminoglycoside-induced, hereditary spastic paraplegia 7, spinocerebellar ataxia type 28, leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome, spastic ataxia 3, pontocerebellar hypoplasia type 6, acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins, congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome, spastic ataxia 4, hyperuricemia-pulmonary hypertension-renal failure-alkalosis syndrome, hereditary spastic paraplegia 55, cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome, Charcot-Marie-Tooth disease recessive intermediate D, autosomal dominant mitochondrial myopathy with exercise intolerance, Charcot-Marie-Tooth disease type 4K, hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome, hereditary spastic paraplegia 77, fatal infantile encephalocardiomyopathy, FASTKD2-related infantile mitochondrial encephalomyopathy, autosomal dominant optic atrophy and peripheral neuropathy, ataxia neuropathy spectrum, maternally-inherited mitochondrial dystonia, Perrault syndrome, hypertrophic cardiomyopathy and renal tubular disease due to mitochondrial DNA mutation, adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy, mitochondrial DNA maintenance syndrome, coenzyme Q10 deficiency, mitochondrial DNA depletion syndrome, periodic paralysis with later-onset distal motor neuropathy, non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy, Zellweger-like syndrome without peroxisomal anomalies, maternally-inherited progressive external ophthalmoplegia, Leber plus disease, encephalopathy due to mitochondrial and peroxisomal fission defect, severe neonatal lactic acidosis due to NFS1-ISD11 complex deficiency

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

22 retrieved; paginated sample, class counts are floors:

9 uncertain significance, 5 benign/likely benign, 3 conflicting classifications of pathogenicity, 2 benign, 1 pathogenic/likely pathogenic, 1 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3780714	NM_032273.4(TMEM126A):c.258del (p.Phe86fs)	TMEM126A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
410	NM_032273.4(TMEM126A):c.163C>T (p.Arg55Ter)	TMEM126A	Pathogenic	criteria provided, multiple submitters, no conflicts
4293764	NM_032273.4(TMEM126A):c.151_154del (p.Asn51fs)	TMEM126A	Likely pathogenic	criteria provided, single submitter
137669	NM_032273.4(TMEM126A):c.96T>G (p.Leu32=)	TMEM126A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
167733	NM_032273.4(TMEM126A):c.385C>G (p.Leu129Val)	TMEM126A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
197361	NM_032273.4(TMEM126A):c.314G>A (p.Arg105Gln)	TMEM126A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
306322	NM_032273.4(TMEM126A):c.-16G>C	LOC130006551	Uncertain significance	criteria provided, single submitter
883047	NM_032273.4(TMEM126A):c.-98C>G	LOC130006551	Uncertain significance	criteria provided, single submitter
1692999	NM_032273.4(TMEM126A):c.329G>A (p.Gly110Asp)	TMEM126A	Uncertain significance	criteria provided, single submitter
196566	NM_032273.4(TMEM126A):c.87G>C (p.Arg29Ser)	TMEM126A	Uncertain significance	criteria provided, multiple submitters, no conflicts
306323	NM_032273.4(TMEM126A):c.487A>G (p.Ile163Val)	TMEM126A	Uncertain significance	criteria provided, multiple submitters, no conflicts
306324	NM_032273.4(TMEM126A):c.502A>G (p.Met168Val)	TMEM126A	Uncertain significance	criteria provided, multiple submitters, no conflicts
880529	NM_032273.4(TMEM126A):c.563C>A (p.Ser188Tyr)	TMEM126A	Uncertain significance	criteria provided, single submitter
883048	NM_032273.4(TMEM126A):c.20A>G (p.Asn7Ser)	TMEM126A	Uncertain significance	criteria provided, multiple submitters, no conflicts
883827	NM_032273.4(TMEM126A):c.368T>C (p.Ile123Thr)	TMEM126A	Uncertain significance	criteria provided, multiple submitters, no conflicts
137670	NM_032273.4(TMEM126A):c.191G>A (p.Arg64His)	TMEM126A	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
137671	NM_032273.4(TMEM126A):c.562T>A (p.Ser188Thr)	TMEM126A	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
196565	NM_032273.4(TMEM126A):c.154A>G (p.Ser52Gly)	TMEM126A	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
215270	NM_032273.4(TMEM126A):c.280+14C>T	TMEM126A	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
215271	NM_032273.4(TMEM126A):c.395+5G>A	TMEM126A	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
262022	NM_032273.4(TMEM126A):c.395+10A>G	TMEM126A	Benign	criteria provided, multiple submitters, no conflicts
306320	NM_032273.4(TMEM126A):c.-69T>A	TMEM126A	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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
TMEM126A	Definitive	Autosomal recessive	optic atrophy	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TMEM126A	Orphanet:227976	Autosomal recessive optic atrophy, OPA7 type

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
TMEM126A	HGNC:25382	ENSG00000171202	Q9H061	Transmembrane protein 126A	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TMEM126A	Transmembrane protein 126A	Protein required for the cotranslational protein quality control in the inner membrane of the mitochondria.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TMEM126A	Other/Unknown	no		TMEM126

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
left ventricle myocardium	1
tibialis anterior	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TMEM126A	257	ubiquitous	marker	left ventricle myocardium, tibialis anterior, deltoid

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TMEM126A	1,518

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TMEM126A	Q9H061	89.75

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
Complex I biogenesis	1	165.5×	0.015	TMEM126A
Respiratory electron transport	1	95.2×	0.015	TMEM126A
Aerobic respiration and respiratory electron transport	1	88.5×	0.015	TMEM126A
Metabolism	1	11.6×	0.086	TMEM126A

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 protein quality control	1	4213.0×	7e-04	TMEM126A
protein insertion into mitochondrial inner membrane from matrix	1	3370.4×	7e-04	TMEM126A
optic nerve development	1	1203.7×	0.001	TMEM126A
toll-like receptor 4 signaling pathway	1	526.6×	0.002	TMEM126A
mitochondrial respiratory chain complex I assembly	1	411.0×	0.002	TMEM126A

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
TMEM126A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TMEM126A	1	Binding:1

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	TMEM126A

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)
TMEM126A	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.