Submissions for variant NM_001943.5(DSG2):c.2617C>T (p.Gln873Ter)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002437210	SCV002745602	likely pathogenic	Cardiovascular phenotype	2016-08-04	criteria provided, single submitter	clinical testing	The p.Q873* variant (also known as c.2617C>T), located in coding exon 15 of the DSG2 gene, results from a C to T substitution at nucleotide position 2617. This changes the amino acid from a glutamine to a stop codon within coding exon 15. Premature stop codons are typically deleterious in nature; however, since this stop codon occurs in the last exon, it is not expected to trigger nonsense-mediated mRNA decay and impacts only the last 247 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time; however, the C-terminal region of DSG2 has been implicated in protein stabilization at the cell surface and in tail-tail interactions (Chen J et al. J Cell Biol. 2012;199(4):699-711). In addition, frameshift and premature truncating alterations beyond this position (e.g., c.3059_3062delAGAG, p.E1020Afs*18) have been reported in association with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) (Christensen AH et al. J Med Genet. 2010;47(11):736-44). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 5956 samples (11912 alleles) with coverage at this position. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003631269	SCV004525200	pathogenic	Arrhythmogenic right ventricular dysplasia 10	2023-07-18	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: 1793874). This variant has not been reported in the literature in individuals affected with DSG2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln873*) in the DSG2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 246 amino acid(s) of the DSG2 protein.