Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001068271 | SCV001233372 | pathogenic | not provided | 2025-01-13 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 569 of the CNGA3 protein (p.Arg569His). This variant is present in population databases (rs201782746, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of achromatopsia (PMID: 11536077, 24148654, 26493561, 30337596). 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: 861698). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. |
| Blueprint Genetics | RCV001074829 | SCV001240429 | pathogenic | Retinal dystrophy | 2019-07-17 | criteria provided, single submitter | clinical testing | |
| Institute of Human Genetics, |
RCV001074829 | SCV005069196 | pathogenic | Retinal dystrophy | 2016-01-01 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004768847 | SCV005381394 | pathogenic | Achromatopsia 2 | 2024-08-05 | criteria provided, single submitter | clinical testing | Variant summary: CNGA3 c.1706G>A (p.Arg569His) 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 1.6e-05 in 251324 control chromosomes. c.1706G>A has been reported in the literature in multiple compound heterozygous individuals affected with Achromatopsia (e.g. Sun_2020). These data indicate that the variant is likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.1705C>T, p.Arg569Cys), supporting the critical relevance of codon 569 to CNGA3 protein function. The following publication has been ascertained in the context of this evaluation (PMID: 32913385). ClinVar contains an entry for this variant (Variation ID: 861698). Based on the evidence outlined above, the variant was classified as pathogenic. |