ClinVar Miner

Submissions for variant NM_001298.3(CNGA3):c.967G>C (p.Ala323Pro)

gnomAD frequency: 0.00033  dbSNP: rs146195955
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000278423 SCV000336492 uncertain significance not provided 2018-03-12 criteria provided, single submitter clinical testing
Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University RCV000761548 SCV000891695 pathogenic Achromatopsia 2 2017-12-30 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001074859 SCV001240461 pathogenic Retinal dystrophy 2019-07-31 criteria provided, single submitter clinical testing
Invitae RCV000278423 SCV001433806 pathogenic not provided 2024-01-06 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 323 of the CNGA3 protein (p.Ala323Pro). This variant is present in population databases (rs146195955, gnomAD 0.09%). This missense change has been observed in individual(s) with cone rod dystrophy and achromatopsia (PMID: 28041643, 30289319; 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: 284032). 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%. This variant disrupts the p.Ala323 amino acid residue in CNGA3. Other variant(s) that disrupt this residue have been observed in individuals with CNGA3-related conditions (PMID: 26493561), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000278423 SCV001822463 pathogenic not provided 2023-04-03 criteria provided, single submitter clinical testing 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: 31725702, 30289319, 32581362, 32783370, 28041643)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000761548 SCV004037983 pathogenic Achromatopsia 2 2023-08-18 criteria provided, single submitter clinical testing Variant summary: CNGA3 c.967G>C (p.Ala323Pro) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Three 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 251488 control chromosomes. c.967G>C has been reported in the literature in multiple individuals affected with Achromatopsia and other CNGA3-related diseases including rod monochromacy and macular degenerations, either being seen with second pathogenic variants or being homozygous (example: Hitti-malin_2022, Mejecase_2020, Sun_2020, Solaki_2022). These data indicate that the variant is very likely to be associated with Achromatopsia 2. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36259723, 32783370, 32913385, 35332618). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (Pathogenic, n=4; Likely pathogenic, n=1; VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000505161 SCV000599089 likely pathogenic Cone dystrophy 2015-01-01 no assertion criteria provided research

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