ClinVar

Description

Variant summary: CNGA3 c.682G>A (p.Glu228Lys) results in a conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 251304 control chromosomes in the gnomAD database, including 2 homozygotes. c.682G>A was found in homozygous state in two siblings with incomplete Achromatopsia (Reuter_ 2008), and in individuals affected with cone dystrophy (Thiadens _2010 and Hitti-malin_CNGA3_HM_2022). In at-least, one of these individuals affected with cone dystrophy authors reported a homozygous variant in CNGB3 (Thiadens _2010). These report(s) do not provide unequivocal conclusions about association of the variant with Achromatopsia 2. At least one publication reports experimental evidence evaluating an impact on protein function. However, it does not provide strong conclusions about the variant association with the disease (Reuter_ 2008). The following publications have been ascertained in the context of this evaluation (PMID: 22995991, 30418171, 36259723, 27535533, 18521937, 26036949, 31456290, 32913385, 20079539). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign/likely benign (n=2), pathogenic/likely pathogenic (n=2) and as uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.