Submissions for variant NM_001943.5(DSG2):c.1773_1774del (p.Cys591_Glu592delinsTer) (rs397516703)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine	RCV000037271	SCV000060928	pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2018-04-23	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000181243	SCV000233522	pathogenic	not provided	2014-04-17	criteria provided, single submitter	clinical testing	At least 12% of patients with autosomal dominant arrhythmogenic right ventricularcardiomyopathy (ARVC) have been reported to have a mutation in the DSG2 gene (McNally E et al., 2009). The c.1773_1774delTG mutation in the DSG2 gene has been previously reported in association with ARVC (Syrris et al., 2007; Sen-Chowdhry et al., 2008; Asimaki et al., 2009). Syrris et al. (2007) identified this mutation 2 individuals in the same family who met TFC for ARVC, and c.1773_1774delTG was not identified in 400 healthy, ethnically-matched control alleles. Furthermore, the c.1773_1774delTG mutation was not observed inapproximately 6300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This mutation causes a shift in reading frame starting at codon Cysteine 591, which creates a premature stop codon at this position, denoted as p.Cys591Stop. This mutation is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift and nonsense mutations in the DSG2 gene have been reported in association with ARVC. In summary, c.1773_1774delTG in the DSG2 gene is interpreted as a disease-causing mutation.