ClinVar

Description

This variant deletes 4 nucleotides in exon 15 of the DSG2 gene, creating a frameshift in the last exon. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a protein product containing altered C-terminal sequence. To our knowledge, functional studies have not been reported for this variant. This variant has been identified in eight unrelated individuals affected with arrhythmogenic cardiomyopathy (PMID: 21397041, 20864495, 23381804, 33821670, 34263121, 36431211) and has been reported to segregate with disease in one of the families (PMID: 21397041). This variant has also been observed in individuals affected with conduction defect (PMID: 21397041), hypertrophic cardiomyopathy (PMID: 34500006), or dilated cardiomyopathy (PMID: 36129056), and in unaffected family members (PMID 21397041) as well as in individuals without history of cardiovascular events (PMID: 33968641, 34135346). Furthermore, the variant has been reported in compound heterozygous state with another DSG2 variant in three individual affected with arrhythmogenic cardiomyopathy (PMID: 37418234). This variant has been identified in 9/249404 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, 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.