ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.3G>A (p.Met1Ile)

gnomAD frequency: 0.00001  dbSNP: rs1021457619
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000814563 SCV000954976 pathogenic Arrhythmogenic right ventricular dysplasia 10 2024-01-17 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the DSG2 mRNA. The next in-frame methionine is located at codon 179. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 17105751, 20829228). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 657863). This variant disrupts the p.Arg49 amino acid residue in DSG2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19151369). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000814563 SCV001369398 likely pathogenic Arrhythmogenic right ventricular dysplasia 10 2019-07-12 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2.
AiLife Diagnostics, AiLife Diagnostics RCV002223950 SCV002503576 pathogenic not provided 2021-08-11 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV002223950 SCV002546000 likely pathogenic not provided 2022-05-01 criteria provided, single submitter clinical testing DSG2: PM2, PS1:Moderate, PVS1:Moderate, PS4:Supporting
All of Us Research Program, National Institutes of Health RCV004001763 SCV004838837 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2023-10-02 criteria provided, single submitter clinical testing This variant alters methionine at codon 1 of the DSG2 mRNA that serves as the translation initiation codon. An alternate in-frame methionine downstream of the initiator methionine occurs at codon 179 in extracellular cadherin domain 2, after signal peptide and propeptide. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two siblings affected with arrhythmogenic right ventricular cardiomyopathy, along with a second missense variant of uncertain significance in the same gene (PMID: 20829228), and in an individual with unspecified phenotype (PMID: 33968641). 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 relevance of loss-of-function DSG2 variants in autosomal dominant arrhythmogenic right ventricular 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.
KardioGenetik, Herz- und Diabeteszentrum NRW RCV000814563 SCV005094557 uncertain significance Arrhythmogenic right ventricular dysplasia 10 2024-06-05 criteria provided, single submitter clinical testing PVS1_moderate, PS4_supporting, PM2_supporting
GeneDx RCV002223950 SCV005414953 likely pathogenic not provided 2024-05-14 criteria provided, single submitter clinical testing Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Reported in patients with ARVC in published literature but detailed clinical information was not included (PMID: 36264615); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20829228, 36264615)

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