Submissions for variant NM_001298.3(CNGA3):c.1705C>T (p.Arg569Cys)

gnomAD frequency: 0.00003  dbSNP: rs757167624

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001068677	SCV001233802	likely pathogenic	not provided	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 569 of the CNGA3 protein (p.Arg569Cys). This variant is present in population databases (rs757167624, gnomAD 0.005%). This missense change has been observed in individual(s) with clinical features of achromatopsia (PMID: 32783370, 35332618). ClinVar contains an entry for this variant (Variation ID: 862038). 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.Arg569 amino acid residue in CNGA3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11536077, 24148654, 26493561, 30337596). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001729790	SCV005062079	pathogenic	Achromatopsia 2	2024-03-13	criteria provided, single submitter	clinical testing	Variant summary: CNGA3 c.1705C>T (p.Arg569Cys) 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 4e-06 in 251326 control chromosomes (gnomAD). c.1705C>T has been reported in the literature in individuals affected with Achromatopsia 2 (Mejecase_2020, Solaki_2022). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in significantly impaired channel function (Solaki_2023). Another missense variant affecting this amino acid (p.Arg569His) has been determined to be pathogenic, suggesting this may be a functionally important residue. The following publications have been ascertained in the context of this evaluation (PMID: 32783370, 35332618). ClinVar contains an entry for this variant (Variation ID: 862038). Based on the evidence outlined above, the variant was classified as pathogenic.
Molecular Genetics Laboratory, Institute for Ophthalmic Research	RCV001729790	SCV001571307	likely pathogenic	Achromatopsia 2	2021-04-15	no assertion criteria provided	research