CACNA1F was first reported in relation to cases of X-linked inheritance of incomplete congenital stationary night blindness in 1998 by two groups (Bech-Hansen et al., PMID: 9662400 and Strom et al., PMID: 9662399). CACNA1F has been noted to be associated with the following disease entities as found in OMIM: Aland Island eye disease (OMIM:300600); X-linked cone-rod dystrophy 3 (OMIM:300476); and incomplete, X-linked congenital stationary night blindness (OMIM:30071). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in the molecular mechanism or inheritance pattern of these diseases. Therefore, these three disease entities have been lumped into a single disease entity, named CACNA1F-related retinopathy for the gene curation of CACNA1F.
17 suspected pathogenic variants (six missense, one in-frame indel, five nonsense, two frameshift, and three splicing) that have been reported in 17 probands across seven publications (PMIDs: 16505158, 11281458, 26992781, 22194652, 12111638, 23714322, and 9662400) are included in this curation. Each proband was a hemizygous male. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be monoallelic loss of function.
This gene-disease association is also supported by experimental evidence that CACNA1F exhibits its highest expression levels in retina tissue, specifically the outer plexiform layer of retina cells (PMIDs: 9662400, 9662399, 11527958). Cacna1f knockout mice exhibit absence of scotopic b-wave and normal a-wave in ERG recordings; significantly reduced calcium signaling; reduced Cacna1f, M-opsin and S-opsin expression in the retina and reduced thickness of the outer plexiform layer of the retina (PMIDs: 16155113, 30445045).
In summary, CACNA1F is definitively associated with X-linked inheritance of CACNA1F-related retinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Retina GCEP on January 5th, 2023 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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