ClinVar Miner

Submissions for variant NM_001298.3(CNGA3):c.1279C>T (p.Arg427Cys) (rs141386891)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Molecular Genetics Laboratory,Institute for Ophthalmic Research RCV000596662 SCV000700223 pathogenic Achromatopsia 2018-03-20 criteria provided, single submitter research
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000596729 SCV000701669 pathogenic not provided 2016-10-28 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000596662 SCV000966883 pathogenic Achromatopsia 2018-06-05 criteria provided, single submitter clinical testing The p.Arg427Cys variant in CNGA3 has been reported in 9 compound heterozygous in dividuals with clinical diagnosis of achromatopsia or cone-rod dystrophy (Wissin ger 2001, Koeppen 2008, Fahim 2013, Taylor 2017), and segregated in 2 affected f amily members (Koeppen 2008, Fahim 2013). This variant has also been identified in 0.15% (47/30754) of South Asian chromosomes, including 1 homozygote, by the G enome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs1 41386891). Although this variant has been seen in the general population, its fr equency is low enough to be consistent with a recessive carrier frequency. In vi tro functional studies provide some evidence that the p.Arg427Cys variant may im pact protein function, resulting in a decreased channel density in the cell memb rane (Koeppen 2008, Muraki-Oda 2007). In summary, this variant is pathogenic for achromatopsia in an autosomal recessive manner. ACMG/AMP Criteria applied: PM3_ VeryStrong; PS3_Moderate; PP3; PP1.
Blueprint Genetics RCV001075180 SCV001240792 pathogenic Retinal dystrophy 2018-11-02 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000596729 SCV001249386 pathogenic not provided 2018-11-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001196267 SCV001366833 pathogenic Achromatopsia 2 2019-09-12 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PP3,PP5.
Invitae RCV000596729 SCV001389552 pathogenic not provided 2020-10-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 427 of the CNGA3 protein (p.Arg427Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs141386891, ExAC 0.2%), including at least one homozygous and/or hemizygous individual. This variant has been observed in individuals and a family affected with achromatopsia or cone dystrophy (PMID: 11536077, 23972307, 28559085, 18445228). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 497256). This variant has been reported to affect CNGA3 protein function (PMID: 18445228). For these reasons, this variant has been classified as Pathogenic.
Human Genetics - Radboudumc,Radboudumc RCV000678541 SCV000804618 uncertain significance Macular dystrophy 2016-09-01 no assertion criteria provided clinical testing
GeneDx RCV000596729 SCV001802563 pathogenic not provided 2021-05-24 no assertion criteria provided clinical testing Published functional studies of this variant demonstrates that cGMP maximum currents of mutant channels were reduced, and the chemical chaperone glycerol significantly enhanced surface expression of mutant channels and macroscopic currents, which may indicate impaired folding and trafficking of the mutant channel protein (Koeppen et al., 2008); 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: 31290651, 30418171, 30653986, 28559085, 30682209, 28341476, 23362848, 24148654, 18445228, 23972307, 24269407, 17652762, 11536077, 15712225, 17693388, 16961972, 19874885, 3039450)

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