Submission Details

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).