Submissions for variant NM_001298.3(CNGA3):c.1688G>A (p.Arg563His)

gnomAD frequency: 0.00004  dbSNP: rs552069173

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254808	SCV000322406	pathogenic	not provided	2016-05-04	criteria provided, single submitter	clinical testing	The R563H pathogenic variant in the CNGA3 gene has been reported previously in two individuals with incomplete achromatopsia and one individual with cone dystrophy who were compound heterozygous for the R563H variant and another missense variant (Wissinger et al., 2001). Functional studies in Xenopus oocytes with the R563H variant show that this variant impacts the function of cyclic nucleotide-gated channels (Liu et al., 2005); additional functional studies in 661W cells with the R563H variant also confirm that the variant impacts the function of the protein (Duricka et al., 2012). The R563H variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R563H variant is a conservative amino acid substitution, which occurs within the cGMP-binding domain at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R563H as a pathogenic variant.
Blueprint Genetics	RCV001074992	SCV001240601	pathogenic	Retinal dystrophy	2017-12-19	criteria provided, single submitter	clinical testing
Invitae	RCV000254808	SCV001420848	pathogenic	not provided	2023-09-01	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CNGA3 function (PMID: 15743887, 17693388). 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. ClinVar contains an entry for this variant (Variation ID: 265467). This missense change has been observed in individual(s) with inherited retinal dystrophy (PMID: 11536077; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs552069173, gnomAD 0.03%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 563 of the CNGA3 protein (p.Arg563His).
Revvity Omics, Revvity	RCV001782754	SCV002023262	likely pathogenic	Achromatopsia 2	2020-05-24	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000254808	SCV002585802	pathogenic	not provided	2022-09-01	criteria provided, single submitter	clinical testing	CNGA3: PM2, PM3, PM5, PS3:Moderate, PS4:Moderate, PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001782754	SCV004222675	pathogenic	Achromatopsia 2	2023-11-15	criteria provided, single submitter	clinical testing	Variant summary: CNGA3 c.1688G>A (p.Arg563His) 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 7.6e-05 in 251250 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1688G>A has been reported in the literature in both homozygous and compound heterozygous individuals affected with Achromatopsia (e.g., Wissinger_2001, Weisschuh_2020, Andersen_2023). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 36980963, 32531858, 11536077). Six submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504957	SCV000599088	likely pathogenic	Abnormality of the eye	2015-01-01	no assertion criteria provided	research	Undetermined rare ocular disorder with frequency of less than eight patients
Clinical Genetics, Academic Medical Center	RCV000254808	SCV001918232	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000254808	SCV001959117	pathogenic	not provided		no assertion criteria provided	clinical testing