ClinVar Miner

Submissions for variant NM_001298.3(CNGA3):c.1669G>A (p.Gly557Arg)

gnomAD frequency: 0.00012  dbSNP: rs104893615
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV001074603 SCV001240194 pathogenic Retinal dystrophy 2019-01-16 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001219847 SCV001391805 pathogenic not provided 2024-01-07 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 557 of the CNGA3 protein (p.Gly557Arg). This variant is present in population databases (rs104893615, gnomAD 0.3%). This missense change has been observed in individual(s) with achromatopsia (PMID: 17265047, 18521937, 25616768; 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: 9476). 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%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CNGA3 function (PMID: 17693388, 18521937). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001219847 SCV001763995 pathogenic not provided 2023-12-08 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect with alteration of cGMP sensitivity, reduced calcium influx, and decreased cell surface expression compared to wild type (PMID: 18521937); 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: 11536077, 32531858, 9662398, 25616768, 17693388, 18521937, 31456290, 31980526)
Ambry Genetics RCV002512958 SCV003552689 likely pathogenic Inborn genetic diseases 2021-08-28 criteria provided, single submitter clinical testing The c.1669G>A (p.G557R) alteration is located in exon 8 (coding exon 7) of the CNGA3 gene. This alteration results from a G to A substitution at nucleotide position 1669, causing the glycine (G) at amino acid position 557 to be replaced by an arginine (R). Based on data from gnomAD, the A allele has an overall frequency of 0.01% (40/282722) total alleles studied. The highest observed frequency was 0.27% (28/10360) of Ashkenazi Jewish alleles. This alteration is one of the most common founder mutations in the Israeli population (Sharon, 2020). It has been reported in association with achromatopsia and other cone photoreceptor disorders in homozygotes and in heterozygotes with an additional CNGA3 alteration (Kohl, 1998; Wissinger, 2001; Wiszniewski, 2007; Reuter, 2008; Zelinger 2015; Matet, 2018). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
OMIM RCV000010084 SCV000030305 pathogenic Achromatopsia 2 1998-07-01 no assertion criteria provided literature only
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000169654 SCV000221181 uncertain significance not specified 2013-10-30 flagged submission clinical testing The Gly557Arg variant in CNGA3 has been identified in 1 compound heterozygous individual with achromatopsia (Kohl 1998). Functional studies indicate this variant may alter protein function (Reuter 2008), though the assay is not clinically validated. In summary, although these data favor pathogenicity of the Gly557Arg variant, additional studies are needed to fully assess its clinical significance.
Sharon lab, Hadassah-Hebrew University Medical Center RCV001002972 SCV001161020 pathogenic Achromatopsia 2019-06-23 no assertion criteria provided research

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