C1QTNF5 was first reported in relation to autosomal dominant retinal degeneration in 2003 (Hayward et al., PMID: 12944416). C1QTNF5-related retinopathy, also referred to in the literature as late-onset retinal degeneration, has symptoms typically appearing in the fifth or sixth decade of life. The first symptom is usually night blindness with punctate yellow-white deposits visible on fundus exam. As the disease progresses, individuals develop severe retinal degeneration in both the central and the peripheral retina as well as choroidal neovascularization, chorioretinal atrophy and sub-RPE deposits.
This curation includes six missense variants that have been reported in eighteen probands in seven publications (PMIDs: 12944416, 28939808, 32036094, 23289492, 38129706, 33669876, 38819368). Of note, the c.489C>G (p.Ser163Arg) variant is the most common variant and was shown to be a founder variant that appears to have originated in south-east Scotland (PMID: 12944416). The mechanism of pathogenicity appears to be dominant negative.
This gene-disease relationship is also supported by experimental evidence that C1QTNF5 is expressed in retinal pigment epithelium cells with some specificity, that disease-associated missense variants affect protein expression and secretion, and that mouse models of the disease and RPE cells derived from induced pluripotent stem cells recapitulate the affected patient phenotype (PMIDs: 12944416, 28939808, 32036094, 34887495, 16123441, 36328299, 21349921, 37440053, 26513502).
In summary, there is definitive evidence supporting the relationship between C1QTNF5 and C1QTNF5-related retinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time without the emergence of contradictory evidence. This classification has been approved by the ClinGen Retina GCEP on September 6th, 2024 (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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