ClinVar Genomic variation as it relates to human health

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM3,PP3,PP4. This variant was detected in homozygous state.

The missense variant p.F547L in CNGA3 (NM_001298.3) has been reported previously in homozygous as well as compound heterozygous state in affected indviduals (Fahim AT et al; Georgiou M et al).It is known to affect protein function (Muraki-Oda S et al). It has been submitted to ClinVar as Pathogenic/Likely Pathogenic. It is present in 45 alleles in heterozygous state in the gnomad database (0.1%) as well as it has been observed in homozygous state in one individual. For these reasons, this variant has been classified as Pathogenic.

Variant summary: CNGA3 c.1641C>A (p.Phe547Leu) results in a non-conservative amino acid change located in the cyclic nucleotide-binding domain (IPR000595) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 251308 control chromosomes in the gnomAD database, including 1 homozygote. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1641C>A has been reported in the literature in numerous homozygous and compound heterozygous individuals affected with Achromatopsia 2 (e.g., Sun_2020). These data indicate that the variant is very likely to be associated with disease. The following publication was ascertained in the context of this evaluation (PMID: 32913385). Seven submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 547 of the CNGA3 protein (p.Phe547Leu). This variant is present in population databases (rs104893617, gnomAD 0.07%). This missense change has been observed in individual(s) with achromatopsia (PMID: 9662398, 11536077, 14757870, 23972307, 30682209). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 9478). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CNGA3 function (PMID: 17693388). For these reasons, this variant has been classified as Pathogenic.

CNGA3: PM3:Very Strong, PM2, PP3, PP4, PS3:Supporting

Published functional studies demonstrate loss of electrophysiological activity in the mutant channel compared to wild type (Matveev et al., 2010; Muraki-Oda et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16961972, 31429209, 32531858, 23972307, 20088482, 9662398, 17693388, 18521937, 25168900, 27040408, 19592100, 11536077, 14757870, 24148654, 16319819, 30682209, 30653986, 31456290, 33562422, 31589614, 34426522, 34449556)