CNGA3 was first reported in relation to autosomal recessive CNGA3-related retinopathy, in a patient with achromatopsia (OMIM:216900) in 1998 (PMID: 9721202). Achromatopsia is a rare congenital autosomal recessive disorder characterized by photophobia, reduced visual acuity, nystagmus, and the complete inability to discriminate between colors. Later studies showed that patients with biallelic pathogenic CNGA3 variants can also have cone-rod dystrophy (PMID: 24903488; PMID: 11536077). Based on the ClinGen Lumping and Splitting guidelines, these disorders are lumped together as CNGA3-related retinopathy. 15 variants (missense, nonsense, frameshift) that have been reported in 11 probands are included in this curation (PMID: 9662398; 27624628; 25637600; 24903488; 25052312). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Notably, four variants (p.R277C, p.R283W, p.R435W, and p.F547L) were reported to account for >40% of all detected variants (PMID: 11536077). Biallelic CNGA3 variants have been demonstrated to segregated in at least 5 families with three or more affected individuals (PMID: 9662398; 25637600; 24903488; 25052312). The mechanism of pathogenicity appears to be loss-of-function. In-vitro studies demonstrated that decreased expression of CNGA3 in the cell membrane of p.Cys319Arg knock-in HEK293 cells possibly as a result of reduced protein stability (PMID: 25052312). In the Muraki-Oda et al study, they identified 32 missense CNGA3 variants with ablated channel functions in an in-vitro study (PMID:17693388). In the Paylou et al study using a CNGA3-/-mouse model, the achromatopsia phenotype was rescued using intravitreal CNGA3 delivery using AAV2.GL, leading to cone-specific expression of CNGA3 protein. In summary, CNGA3 is definitively associated with autosomal recessive CNGA3-related retinopathy. This has been repeated demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
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