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

gnomAD frequency: 0.00033  dbSNP: rs146195955

Total submissions: 7

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