OPA3

protein-coding

outer mitochondrial membrane lipid metabolism regulator OPA3

Gene summary

The mouse ortholog of this protein co-purifies with the mitochondrial inner membrane. Mutations in this gene have been shown to result in 3-methylglutaconic aciduria type III and autosomal dominant optic atrophy and cataract. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

MANE transcript

NM_025136.4

Inheritance

AD, AR

ClinVar variants

P:42U:161B:125

Top phenotype

3-methylglutaconic aciduria, type III; Optic atrophy 3, autosomal dominant

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr19:45,527,767-45,602,212

External References & Databases

Ensembl (ENSG00000125741)

Transcript & Mutation Effects

hg38 • Region Span ~74.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

optic atrophy 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008133

Submitter: PanelApp Australia

3-methylglutaconic aciduria type 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009787

Submitter: PanelApp Australia

3-methylglutaconic aciduria type 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009787

Submitter: Myriad Women's Health

3-methylglutaconic aciduria type 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009787

Submitter: G2P

3-methylglutaconic aciduria type 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009787

Submitter: Labcorp Genetics (formerly Invitae)

optic atrophy 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008133

Submitter: Labcorp Genetics (formerly Invitae)

optic atrophy 3DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008133

Submitter: G2P

optic atrophy 3MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0008133

Submitter: ClinGen

*OPA3* was first reported in relation to autosomal dominant optic atrophy 3 in 2004 (Reynier et al; PMID: 15342707). *OPA3* encodes the lipid metabolism regulator, OPA3, which was initially thought to be mitochondrial inner membrane (MIM) protein, but later shown to be a mitochondrial outer membrane (MOM) protein (Ryu et al, 2010; PMID: 20372962). The function of this protein is not clearly understood, but involved in mitochondrial processes. Optic atrophy 3 (also known as autosomal dominant optic atrophy with cataract, ADOAC) is characterized by optic atrophy with onset mostly in childhood, decreased visual acuity, cerebellar ataxia, areflexia, mild extrapyramidal signs, and cataract, among other features. OMIM entities: AD optic atrophy with cataract; Costeff syndrome/3-methylglutaconic aciduria type 3 (MGA3). The two disease entities are characterized by several overlapping features. While optic atrophy is a clinical feature that is part of the spectrum associated with 3-methyglutaconic aciduria type III, the optic atrophy 3 with cataract entity also includes certain distinct phenotypes. The inheritance patterns (AR for MGA type III and AD for optic atrophy 3) as well as the molecular mechanism (biallelic loss of function for MGA type III and gain of function for optic atrophy 3) for the two entities are different. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, the following disease entities have been split into two disease entities, autosomal recessive 3-methylglutaconic aciduria type 3 (Costeff syndrome) and the autosomal dominant optic atrophy 3 with cataract. Only the AD optic atrophy 3 with cataract is curated by the Glaucoma/Neuro-Op GCEP. The AR metabolic disease will be curated by another relevant GCEP. Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least five variants (missense), including one recurrent variant, in this gene have been reported in at least 13 probands in 6 publications (PMID: 28050599, 25159689, 22797356, 31119193, 24136862, 15342707). One recurrent variant, Gln105Glu, has been observed as a de novo variant in 1 individual and in 8 other unrelated individuals (all likely European origin, but without explicit ancestry information), along with segregation data. Haplotype analysis across 3 families in one study revealed a common disease genotype only in two families, but not in the third, indicating that the variant likely arose independently in other families, and hence recurrence of this variant has been scored half of the default points. Limited experimental evidence is available in the literature. OPA3 is shown to localize to the mitochondria, specifically in the outer membrane (PMID: 20372962). Functional evidence in HeLa cells show that *OPA3* overexpression induces mitochondrial fragmentation (PMID: 20372962). Analyses in patient fibroblasts with an *OPA3* variant shows a mitochondrial coupling defect, similar to fibroblasts with *OPA1* and LHON alterations. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Glaucoma and Neuro-Ophthalmology Gene Curation Expert Panel on April 18th, 2024 (SOP Version 10).

3-methylglutaconic aciduria type 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009787

Submitter: Natera

optic atrophy 3DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008133

Submitter: Natera

3-methylglutaconic aciduria type 3SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009787

Submitter: Orphanet

optic atrophy 3SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008133

Submitter: Orphanet

Clinical Genomic Database (CGD)

3-methylglutaconic aciduria, type III; Optic atrophy 3, autosomal dominantAD/AR

Manifestation: Biochemical; Neurologic; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 2494568; 7510656; 11668429; 12126933; 15342707; 22776096; 23700088; 24749080; 26190011

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to OPA3 variants in ClinVar

11 Conditions Cataloged

3-Methylglutaconic aciduria type 3Total: 346

Optic atrophy 3Total: 312

not providedTotal: 49

Inborn genetic diseasesTotal: 23

not specifiedTotal: 11

OPA3-related disorderTotal: 11

3-Methylglutaconic aciduriaTotal: 1

Optic atrophyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_025136.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	121 clinvar		122
missense	3 clinvar	7 clinvar	152 clinvar	4 clinvar		166
nonsense	2 clinvar	9 clinvar	2 clinvar			13
start loss		1 clinvar				1
frameshift	1 clinvar	15 clinvar	6 clinvar			22
splice donor/acceptor (+/-2bp)	3 clinvar	1 clinvar				4
Total	9	33	161	125	0	328

Highest pathogenic variant AF is 0.000013139914

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 10 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_025136.4	RefSeq	NP_079412.1	2	MANE Select
ENST00000263275.5	Ensembl	ENSP00000263275.4	2	MANE Select
NM_001017989.3	RefSeq	NP_001017989.2	2	Standard
ENST00000323060.4	Ensembl	ENSP00000319817.3	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

visual perception
regulation of lipid metabolic process
regulation of growth
response to stimulus
neuromuscular process

Cellular Component

mitochondrion

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000323060
Coding exons: 2
Length: 74786
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0520	109	111	0.986	0.00000570	1144
Missense (PolyPhen)		43	35.898	1.1978		399
Synonymous	0.122	51	52.1	0.978	0.00000285	393
Loss of Function	1.48	0	2.54	0.00	1.21e-7	26

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May play some role in mitochondrial processes.;
Disease: DISEASE: Optic atrophy 3 (OPA3) [MIM:165300]: A condition that features progressive visual loss in association with optic atrophy. Atrophy of the optic disk indicates a deficiency in the number of nerve fibers which arise in the retina and converge to form the optic disk, optic nerve, optic chiasm and optic tracts. OPA3 is associated with cataract and a neurologic disorder characterized by extrapyramidal signs and ataxia. {ECO:0000269|PubMed:15342707}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.158

Intolerance Scores

LoFtool: 0.318
RVIS EVS: 0.37
RVIS percentile EVS: 75.12

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.343

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium