Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000155624 | SCV000205332 | uncertain significance | not specified | 2017-12-07 | criteria provided, single submitter | clinical testing | Variant classified as Uncertain Significance - Favor Pathogenic. The p.Cys496fs variant in DSG2 has been identified by our laboratory in 1 Caucasian individual with possible ARVC including biventricular dilation and VT; however this individ ual also carried a likely pathogenic variant in TTN. The p.Cys496fs variant was absent from large population studies. This variant is predicted to cause a frame shift, which alters the protein?s amino acid sequence beginning at position 496 and leads to a premature termination codon 40 amino acids downstream. This alter ation is then predicted to lead to a truncated or absent protein. Frameshift and other loss of function variants in DSG2 gene have been reported in individuals with ARVC. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Cys496fs variant is uncertain. |
Labcorp Genetics |
RCV000642310 | SCV000763979 | pathogenic | Arrhythmogenic right ventricular dysplasia 10 | 2021-04-04 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in DSG2 are known to be pathogenic (PMID: 23381804, 23911551). This variant has not been reported in the literature in individuals with DSG2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Cys496Trpfs*40) in the DSG2 gene. It is expected to result in an absent or disrupted protein product. |
Gene |
RCV001657888 | SCV001874875 | likely pathogenic | not provided | 2023-10-09 | criteria provided, single submitter | clinical testing | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published in association with DSG2-related disorders to our knowledge; This variant is associated with the following publications: (PMID: 31638835) |
Ambry Genetics | RCV002390355 | SCV002702654 | pathogenic | Cardiovascular phenotype | 2022-12-07 | criteria provided, single submitter | clinical testing | The c.1487dupG pathogenic mutation, located in coding exon 11 of the DSG2 gene, results from a duplication of G at nucleotide position 1487, causing a translational frameshift with a predicted alternate stop codon (p.C496Wfs*40). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. |
All of Us Research Program, |
RCV003998283 | SCV004822204 | uncertain significance | Arrhythmogenic right ventricular cardiomyopathy | 2023-04-03 | criteria provided, single submitter | clinical testing | This variant causes a duplication of one nucleotide in exon 11 of the DSG2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in 13 individuals from a cohort of participants undergoing whole exome sequencing (PMID: 31638835). None of these individuals had an existing diagnosis of arrhythmogenic right ventricular cardiomyopathy or abnormal ECG or echocardiogram findings. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, clinical significance of loss-of-function DSG2 variants in autosomal dominant arrhythmogenic cardiomyopathy is not yet clearly established. 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. |