ClinVar Miner

Submissions for variant NM_001148.6(ANK2):c.5758G>A (p.Gly1920Arg) (rs140189724)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000617415 SCV000738136 uncertain significance Cardiovascular phenotype 2017-08-17 criteria provided, single submitter clinical testing The p.G1920R variant (also known as c.5758G>A), located in coding exon 38 of the ANK2 gene, results from a G to A substitution at nucleotide position 5758. This exon is expressed solely in brain (Mohler PJ et al. Circulation, 2007 Jan;115:432-41). This alteration has been reported in one individual with Brugada syndrome; however, clinical details were limited (Allegue C et al. PLoS ONE, 2015 Jul;10:e0133037). The glycine at codon 1920 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.<br />
Invitae RCV001055077 SCV001219442 uncertain significance Long QT syndrome 2020-09-09 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 1920 of the ANK2 protein (p.Gly1920Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs140189724, ExAC 0.01%). This variant has been observed in individual(s) with clinical features of Brugada syndrome (PMID: 26230511). ClinVar contains an entry for this variant (Variation ID: 519494). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Clinical Services Laboratory,Illumina RCV001149833 SCV001310829 uncertain significance Cardiac arrhythmia, ankyrin B-related 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001264521 SCV001442716 likely benign not specified 2020-10-26 criteria provided, single submitter clinical testing Variant summary: ANK2 c.5758G>A (p.Gly1920Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 250626 control chromosomes, predominantly at a frequency of 0.00016 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 24 fold of the estimated maximal expected allele frequency for a pathogenic variant in ANK2 causing Long QT Syndrome phenotype (6.7e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.5758G>A has been reported in the literature in individuals affected with Brugada Syndrome (Allegue_2015, Campuzano_2019). These reports do not provide unequivocal conclusions about association of the variant with Long QT Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.