Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001871958 | SCV002145332 | pathogenic | not provided | 2023-10-03 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 331 of the CNGA3 protein (p.Gly331Glu). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of CNGA3-related disease (PMID: 35332618; Invitae). 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: 1064498). 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.Gly331 amino acid residue in CNGA3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25943428). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001729898 | SCV005380602 | likely pathogenic | Achromatopsia 2 | 2024-08-12 | criteria provided, single submitter | clinical testing | Variant summary: CNGA3 c.992G>A (p.Gly331Glu) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) 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 251480 control chromosomes. c.992G>A has been reported in the literature in at least one individual affected with Achromatopsia without reported genotype (e.g. Solaki_2022). This report does not provide unequivocal conclusions about association of the variant with Achromatopsia 2. At least one publication reports experimental evidence evaluating an impact on protein function. In an aequorin-based luminescence bioassay, the variant showed <10% of normalized overall luminescence activity compared to WT in vitro (e.g. Solaki_2023). The following publications have been ascertained in the context of this evaluation (PMID: 37689994, 35332618). ClinVar contains an entry for this variant (Variation ID: 1064498). Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Molecular Genetics Laboratory, |
RCV001729898 | SCV001571287 | likely pathogenic | Achromatopsia 2 | 2021-04-15 | no assertion criteria provided | research |