Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| New York Genome Center | RCV002275682 | SCV002564372 | likely pathogenic | Arrhythmogenic right ventricular dysplasia 10; Dilated cardiomyopathy 1BB | 2021-09-26 | criteria provided, single submitter | clinical testing | The inherited c.2990del (p.Gly997ValfsTer20) variant identified in the DSG2 gene is the deletion of a single nucleotide at c.2990, which is predicted to lead to a frameshift at amino acid 997/ 1119 (exon 15/15) and result in the premature termination of the protein approximately 20 amino acids downstream of the variant. This variant is found with low frequency in gnomAD(V2.1.1) (1 heterozygote, 0 homozygotes; allele frequency:4.01e-6) suggesting it is not a common benign variant in the populations represented in that database. This variant is absent from ClinVar, although frameshift variants downstream of the one identified here have been reported as Pathogenic and Likely Pathogenic (VarIDs:870737, 1069061, 199827, others). The p.Gly997ValfsTer20 variant identified here has been reported in one pediatric patient with a family history of ARVD, but with yet uncertain cardiac phenotype [PMID:21723241], and in three additional individuals with ARVD, one of whom had an additional DSG2 nonsense variant in trans [PMID:24070718]. Additional affected individuals have been reported with nonsense or frameshift variants downstream of the one identified here, suggesting a critical role for the C-terminal regions of DSG2 [PMID:34135346, 33821670, 26743238]. The p.Gly997ValfsTer20 variant occurs within the fifth Desmoglein repeat of the protein and is predicted to remove most of that repeat as well as the 6th Desmoglein repeat (UniProtKB:Q14126). In yeast model systems, the series of cadherin repeats within the C-terminal region (also called the DSG Unique Region (DUR)) are criticalfor protein-protein interactions, as well as DSG localization and function [PMID:23128240]. Introduction of a frameshift variant similar to the one identified here abrogated DUR-DUR interactions and resulted in significant mislocalization of the protein and impaired delivery and/or increased internalization of the protein [PMID:23128240]. The inherited c.2990del (p.Gly997ValfsTer20) variant identified in the DSG2 gene of this individual is reported as Likely Pathogenic |
| Labcorp Genetics |
RCV003096228 | SCV003442530 | pathogenic | Arrhythmogenic right ventricular dysplasia 10 | 2023-09-27 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 1701778). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the DSG2 protein in which other variant(s) (p.Glu1020Alafs*18) have been determined to be pathogenic (PMID: 20864495, 21397041, 23381804). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Experimental studies have shown that this premature translational stop signal affects DSG2 function (PMID: 23128240). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. This premature translational stop signal has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 21723241, 24070718). This sequence change creates a premature translational stop signal (p.Gly997Valfs*20) in the DSG2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 122 amino acid(s) of the DSG2 protein. This variant is not present in population databases (gnomAD no frequency). |