The KCNV2 gene was first reported in relation to "cone dystrophy with supernormal rod responses" (CDSRR) with an autosomal recessive mode of inheritance in 2005 (PMID: 15722315, PMID:16909397). This disease is also referred to as retinal cone dystrophy 3B (MIM#: 610356). Probands have also been reported with similar diagnoses such as cone dystrophy or "achromatopsia and congenital cone dysfunction" (PMID: 18235024), so all of these cases have been lumped for the purposes of this gene curation under the more general disease term KCNV2-related retinopathy.
This curation has scored genetic evidence from the first paper linking the phenotype with variants in the KCNV2 gene by linkage analysis and Sanger sequencing in one family, followed by the analysis of a cohort of 10 additional probands (PMID:16909397). These probands have been included in the present curation, along with others from a cohort of 17 patients from 13 families ((PMID: 18235024). Numerous publications have collectively reported over 180 disease-causing variants, all of which are inferred to lead to loss-of-function. The variant types range from missense, in-frame indels, nonsense, and frameshift variants to large deletions and complex rearrangements. More cases were availbable in the literature, but the maximum score for genetic evidence had already been reached.
The KCNV2 encodes the regulatory subunit (Kv8.2) of voltage-gated potassium channels. These channels control the excitability of electrically active cells, and are made up of 4 subunits that create the central ion channel (PMID: 34063002). Disease-associated missense variants in yeast two-hybrid studies exhibit defective protein interaction with the KCNB1 gene product Kv2.1 (PMID: 21882291), consistent with a loss-of-function mechanism of pathogenicity. Disease-associated missense variants also exhibit loss of interaction and altered electrophysiological function when exogenously expressed in HEK293 cells (PMID: 23115240). Kcnv2 knockout mice exhibit a depressed a-wave and elevated b-wave, recapitulating the human abnormal response, accompanied by retinal changes including increased TUNEL-positive cells (PMID: 30820446).
In summary, KCNV2 is definitively associated with KCNV2-related retinopathy. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a definitive classification. This classification has been approved by the ClinGen Retina GCEP on September 7th, 2023 (SOP Version 10).
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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