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

dbSNP: rs397516703

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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	2021-07-12	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; A different nucleotide change (c.1773 T>A) leading to the same nonsense variant has been reported in HGMD (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 27535533, 31402444, 25157032, 21606390, 17105751, 19279339, 19095136)
AiLife Diagnostics, AiLife Diagnostics	RCV000181243	SCV002501801	pathogenic	not provided	2022-01-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003517132	SCV004297822	pathogenic	Arrhythmogenic right ventricular dysplasia 10	2023-07-29	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 44286). This premature translational stop signal has been observed in individual(s) with clinical features of DSG2-related conditions (PMID: 17105751). This variant is present in population databases (rs774105846, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Cys591*) in the DSG2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DSG2 are known to be pathogenic (PMID: 17105751, 31386562).
All of Us Research Program, National Institutes of Health	RCV000037271	SCV004836346	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2023-12-18	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 12 of the DSG2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least three unrelated individuals affected with arrhythmogenic cardiomyopathy (PMID: 17105751, 19095136, 25157032) and has been shown to segregate with disease in two families (PMID: 17105751, 25157032). The p.Cys591* variant has been identified in a 45 year old patient with ARVC (PMID: 19279339). This variant has been identified in 1/249168 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV005328200	SCV005996222	pathogenic	Cardiovascular phenotype	2025-01-03	criteria provided, single submitter	clinical testing	The c.1773_1774delTG pathogenic mutation, located in coding exon 12 of the DSG2 gene, results from a deletion of two nucleotides at nucleotide positions 1773 to 1774, causing a translational frameshift with a predicted alternate stop codon (p.C591*). This variant was reported in individual(s) with features consistent with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Syrris P et al. Eur Heart J, 2007 Mar;28:581-8; Brun F et al. J Med Genet, 2014 Oct;51:669-76). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.