Submissions for variant NM_001943.5(DSG2):c.2372_2373del (p.Thr791fs)

dbSNP: rs794728098

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181250	SCV000233529	pathogenic	not provided	2014-10-30	criteria provided, single submitter	clinical testing	At least 12% of patients with ARVC have been reported to have a mutation in the DSG2 gene (McNally E et al., 2009). Although the c.2372_2373delCA mutation in the DSG2 gene has not been reported to our knowledge, this mutation causes a shift in reading frame starting at codon Threonine 791, changing it to a Serine, and creating a premature stop codon at position 14 of the new reading frame, denoted p.Thr791SerfsX14. Other frameshift mutations in the DSG2 gene have been reported in association with ARVC
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852264	SCV002228273	pathogenic	Arrhythmogenic right ventricular dysplasia 10	2023-05-15	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). 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: 199831). This variant has not been reported in the literature in individuals affected with DSG2-related conditions. This sequence change creates a premature translational stop signal (p.Thr791Serfs*14) in the DSG2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 328 amino acid(s) of the DSG2 protein. For these reasons, this variant has been classified as Pathogenic.