ClinVar Genomic variation as it relates to human health

Variant summary: CNGA3 c.1307G>A (p.Arg436Gln) results in a conservative amino acid change in the encoded protein sequence. This alters a well-conserved residue (HGMD) in which another missense variant (p.Arg436Trp) has been classified as pathogenic by our lab and other ClinVar submitters. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 250734 control chromosomes (gnomAD). c.1307G>A has been reported in the literature in individuals affected with inherited retinal disease including cone-rod dystrophy (Li_2014, Huang_2016, Wang_2019). In one proband, the variant was found in trans with a pathogenic variant, alghough another missense variant of uncertain significance was found in cis. These reports do not provide unequivocal conclusions about association of the variant with Achromatopsia 2. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24903488, 31106028, 26992781). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 436 of the CNGA3 protein (p.Arg436Gln). This variant is present in population databases (rs767083685, gnomAD 0.06%). This missense change has been observed in individual(s) with achromatopsia (PMID: 24903488). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CNGA3 protein function. This variant disrupts the p.Arg436 amino acid residue in CNGA3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11536077, 17693388, 25943428, 26992781). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.