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

dbSNP: rs794728084

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181209	SCV000233487	uncertain significance	not provided	2023-10-19	criteria provided, single submitter	clinical testing	Has not been previously published in association with DSG2-related disease to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 144 amino acids are lost.; This variant is associated with the following publications: (PMID: 33684294)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000687936	SCV000815529	pathogenic	Arrhythmogenic right ventricular dysplasia 10	2022-03-19	criteria provided, single submitter	clinical testing	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: 199801). This variant has not been reported in the literature in individuals affected with DSG2-related conditions. This variant is present in population databases (rs794728084, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Val975*) in the DSG2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 144 amino acid(s) of the DSG2 protein.
All of Us Research Program, National Institutes of Health	RCV003996612	SCV004836115	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2023-11-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004619212	SCV005117140	uncertain significance	Cardiovascular phenotype	2024-05-13	criteria provided, single submitter	clinical testing	The c.2923delG variant, located in coding exon 15 of the DSG2 gene, results from a deletion of one nucleotide at nucleotide position 2923, causing a translational frameshift with a predicted alternate stop codon (p.V975*). This alteration occurs at the 3' terminus of theDSG2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 13% of the protein. The exact functional effect of this alteration is unknown. Based on the available evidence, the clinical significance of this variant remains unclear.