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Biallelic variants in <jats:italic>ACO2<\/jats:italic> are purported to cause two distinct disorders: infantile cerebellar\u2010retinal degeneration (ICRD) which is characterized by CNS abnormalities, neurodevelopmental phenotypes, optic atrophy and retinal degeneration; and optic atrophy 9 (OPA9), characterized by isolated ophthalmologic phenotypes including optic atrophy and low vision. However, some doubt remains as to whether biallelic <jats:italic>ACO2<\/jats:italic> variants can cause isolated ophthalmologic phenotypes. A review of the literature revealed five individuals from three families who carry biallelic <jats:italic>ACO2<\/jats:italic> variants whose phenotypes are consistent with OPA9. Here, we describe a brother and sister with OPA9 who are compound heterozygous for novel missense variants in <jats:italic>ACO2<\/jats:italic>; c.[487G&gt;T];[1894G&gt;A], p.[(Val163Leu)];[(Val632Met)]. A review of pathogenic <jats:italic>ACO2<\/jats:italic> variants revealed that those associated with OPA9 are distinct from those associated with ICRD. Missense variants associated with either OPA9 or ICRD do not cluster in distinct ACO2 domains, making it difficult to predict the severity of a variant based on position alone. We conclude that biallelic variants in <jats:italic>ACO2<\/jats:italic> can cause the milder OPA9 phenotype, and that the OPA9\u2010related <jats:italic>ACO2<\/jats:italic> variants identified to date are distinct from those that cause ICRD.<\/jats:p>","DOI":"10.1002\/ajmg.a.61634","type":"journal-article","created":{"date-parts":[[2020,5,25]],"date-time":"2020-05-25T07:51:13Z","timestamp":1590393073000},"page":"1960-1966","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Recessive <scp><i>ACO2<\/i><\/scp> variants as a cause of isolated ophthalmologic phenotypes"],"prefix":"10.1002","volume":"182","author":[{"given":"Shelley","family":"Gibson","sequence":"first","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahshid S.","family":"Azamian","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"},{"name":"Texas Children's Hospital  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0707-657X","authenticated-orcid":false,"given":"Seema R.","family":"Lalani","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas USA"},{"name":"Texas Children's Hospital  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly G.","family":"Yen","sequence":"additional","affiliation":[{"name":"Texas Children's Hospital  Houston Texas USA"},{"name":"Department of Ophthalmology Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V. 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