Submissions for variant NM_001943.5(DSG2):c.2343_2344insAAGA (p.Ser782fs)

dbSNP: rs1252006527

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001180681	SCV001345676	uncertain significance	Cardiomyopathy	2023-05-10	criteria provided, single submitter	clinical testing	This variant inserts 4 nucleotides in exon 15 of the DSG2 gene, creating a frameshift and premature translation stop signal 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, this variant has not been reported in individuals affected with DSG2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001875995	SCV002186204	pathogenic	Arrhythmogenic right ventricular dysplasia 10	2022-03-08	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with DSG2-related conditions. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the DSG2 protein in which other variant(s) (p.Glu1020Alafs*18) have been determined to be pathogenic (PMID: 20864495, 21397041, 23381804). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 921330). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser782Lysfs*5) in the DSG2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 337 amino acid(s) of the DSG2 protein.
All of Us Research Program, National Institutes of Health	RCV004006680	SCV004821786	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2023-05-30	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This variant inserts 4 nucleotides in exon 15 of the DSG2 gene, creating a frameshift and premature translation stop signal. This truncation occurs in the last exon that encodes a cytoplasmic region and is expected to result in an absent or non-functional protein product. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). The role of DSG2 truncation variants in cardiomyopathy is not clearly established. Available evidence is insufficient to determine the pathogenicity of this variant conclusively.