ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.3039C>A (p.Tyr1013Ter) (rs539821357)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769518 SCV000900913 uncertain significance Cardiomyopathy 2016-11-30 criteria provided, single submitter clinical testing
GeneDx RCV000431080 SCV000535422 likely pathogenic not provided 2016-12-21 criteria provided, single submitter clinical testing The Y1013X variant in the DSG2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The Y1013X variant was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is predicted to cause loss of normal protein function either protein truncation, as the last 106 amino acids of the protein are lost. Protein truncating variants downstream of this variant have been reported in the Human Gene Mutation Database in association with ARVC (Stenson et al., 2014), supporting the pathogenicity of more upstream truncating variants. Therefore, we interpret Y1013X as a likely pathogenic variant; however, the possibility it is a rare benign variant cannot be completely excluded.
Invitae RCV000642320 SCV000763989 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 10 2017-09-08 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the DSG2 gene (p.Tyr1013*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 106 amino acids of the DSG2 protein. This variant is present in population databases (rs539821357, ExAC 0.06%). This variant has not been reported in the literature in individuals with DSG2-related disease. ClinVar contains an entry for this variant (Variation ID: 392196). A different truncation downstream of this variant (p.Glu1020Alafs*18) has been determined to be pathogenic (PMID: 21397041, 20864495, 23381804). This suggests that deletion of this region of the DSG2 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.

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