ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.875G>A (p.Arg292His) (rs185821167)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037318 SCV000060975 uncertain significance not specified 2018-01-17 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Invitae RCV000205277 SCV000261997 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2019-10-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 292 of the DSG2 protein (p.Arg292His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs185821167, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with DSG2-related disease. ClinVar contains an entry for this variant (Variation ID: 44330). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
GeneDx RCV000767197 SCV000622048 uncertain significance not provided 2017-11-06 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DSG2 gene. The R292H variant has been reported as a homozygous variant in several members of one family who had ARVC; however, these individuals were also homozygous for another variant in the DSG2 gene and the individuals that were heterozygous for the R242H variant had normal echocardiograms (Jiménez-Jáimez et al., 2014). The R292H variant is observed in 11/34416 (0.03%) alleles from individuals of Latino ancestry in large population cohorts (Lek et al., 2016). The R292H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to arginine (R) are tolerated across species. Nevertheless, in silico analysis predicts this variant is probably damaging to the protein structure/function.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770549 SCV000901996 uncertain significance Cardiomyopathy 2016-05-16 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000767197 SCV001501200 uncertain significance not provided 2020-09-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000770549 SCV001735670 uncertain significance Cardiomyopathy 2020-12-11 criteria provided, single submitter clinical testing This missense variant replaces arginine with histidine at codon 292 of the DSG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 24/280756 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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.