ClinVar Miner

Submissions for variant NM_133497.4(KCNV2):c.1381G>A (p.Gly461Arg)

dbSNP: rs149648640
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000030809 SCV000915279 pathogenic Cone dystrophy with supernormal rod response 2018-10-23 criteria provided, single submitter clinical testing The KCNV2 c.1381G>A (p.Gly461Arg) missense variant has been reported in at least four studies in which it is found in a total of 15 individuals affected with retinal cone dystrophy including six homozygotes (three of whom are independent) and nine compound heterozygotes (eight of whom are indepedent) (Wissinger et al. 2008; Wissinger et al. 2011; Friedburg et al. 2011; Fujinami et al. 2013). The p.Gly461Arg variant was absent from a total of 159 controls (Wissinger et al. 2008; Wissinger et al. 2011) and is reported at a frequency of 0.00058 in the European American population of the Exome Sequencing Project. The variant is present in a conserved residue in the Gly-Tyr-Gly motif, an important functional domain in the pore region of the protein. Functional studies conducted in COS7 cells showed that the variant protein is trafficked to the membrane and likely forms heteromeric channels; however, current flow through these channels was reduced relative to that through those formed with the wild type form of the protein (Smith et al. 2012). Based on the collective evidence, the p.Gly461Arg variant is classified as pathogenic for retinal cone dystrophy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Blueprint Genetics RCV001075668 SCV001241296 pathogenic Retinal dystrophy 2019-03-25 criteria provided, single submitter clinical testing
Invitae RCV001245357 SCV001418640 pathogenic not provided 2023-12-18 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 461 of the KCNV2 protein (p.Gly461Arg). This variant is present in population databases (rs149648640, gnomAD 0.03%). This missense change has been observed in individual(s) with cone dystrophy with supernormal rod electroretinogram (PMID: 17896311, 18400204). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 37247). 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 KCNV2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects KCNV2 function (PMID: 23115240). For these reasons, this variant has been classified as Pathogenic.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV001270117 SCV001448979 pathogenic Abnormality of the nervous system; Nystagmus 2018-01-24 criteria provided, single submitter clinical testing
Institute of Medical Molecular Genetics, University of Zurich RCV000030809 SCV001548040 likely pathogenic Cone dystrophy with supernormal rod response 2021-01-30 criteria provided, single submitter clinical testing
Preventiongenetics, part of Exact Sciences RCV003430644 SCV004116485 pathogenic KCNV2-related condition 2022-10-26 criteria provided, single submitter clinical testing The KCNV2 c.1381G>A variant is predicted to result in the amino acid substitution p.Gly461Arg. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with retinal cone dystrophy (Thiagalingam et al. 2007. PubMed ID: 17896311; Friedburg et al. 2011. PubMed ID: 21911584; Fujinami et al. 2013. PubMed ID: 23885164; Table S2 in Weisschuh et al. 2020. PubMed ID: 32531858). This variant is reported in 0.024% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-2729470-G-A). This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/37247). Given the evidence, we interpret c.1381G>A (p.Gly461Arg) as pathogenic.
OMIM RCV000030809 SCV000053480 pathogenic Cone dystrophy with supernormal rod response 2011-12-01 no assertion criteria provided literature only
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV001245357 SCV001958250 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV001245357 SCV001972475 pathogenic not provided no assertion criteria provided clinical testing

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