ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.2923del (p.Leu974_Val975insTer) (rs794728084)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181209 SCV000233487 likely pathogenic not provided 2018-02-02 criteria provided, single submitter clinical testing Although the c.2923delG likely pathogenic variant in the DSG2 gene has not been reported to our knowledge, this variant has been identified in one other unrelated individual referred for ARVC genetic testing at GeneDx. The c.2923delG variant causes a shift in reading frame resulting in a nonsense change at codon 975, denoted p.Val975Stop. This likely pathogenic variant is expected to result in an abnormal, truncated protein product with loss of the last 144 amino acid residues. Multiple other frameshift and nonsense variants in the DSG2 gene have been reported in Human Gene Mutation Database in association with ARVC (Stenson et al., 2014). Furthermore, the c.2923delG variant has not been observed in large population cohorts (Lek et al., 2016).
Invitae RCV000687936 SCV000815529 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 10 2018-06-12 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the DSG2 gene (p.Val975*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 144 amino acids of the DSG2 protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with DSG2-related disease. ClinVar contains an entry for this variant (Variation ID: 199801). A different truncation (p.Glu1020Alafs*18) that lies downstream of this variant 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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