Total submissions: 9
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Illumina Laboratory Services, |
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, |
RCV001270117 | SCV001448979 | pathogenic | Abnormality of the nervous system; Nystagmus | 2018-01-24 | criteria provided, single submitter | clinical testing | |
Institute of Medical Molecular Genetics, |
RCV000030809 | SCV001548040 | likely pathogenic | Cone dystrophy with supernormal rod response | 2021-01-30 | criteria provided, single submitter | clinical testing | |
Preventiongenetics, |
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, |
RCV001245357 | SCV001958250 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV001245357 | SCV001972475 | pathogenic | not provided | no assertion criteria provided | clinical testing |