Submissions for variant NM_001943.5(DSG2):c.3059_3062del (p.Glu1020fs)

dbSNP: rs397516706

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV000208503	SCV000263862	pathogenic	Primary dilated cardiomyopathy	2015-04-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000242452	SCV000320489	likely pathogenic	Cardiovascular phenotype	2022-10-31	criteria provided, single submitter	clinical testing	The c.3059_3062delAGAG variant, located in coding exon 15 of the DSG2 gene, results from a deletion of 4 nucleotides between nucleotide positions 3059 and 3062, causing a translational frameshift with a predicted alternate stop codon (p.E1020Afs*18). This alteration occurs at the 3' terminus of theDSG2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 99 amino acids (8.9%) of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This variant has been described in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) or features consistent with ARVC and an individual described as having left-dominant arrhythmogenic cardiomyopathy (Christensen AH et al. J Med Genet. 2010;47(11):736-44; Lahtinen AM et al. Heart Rhythm. 2011;8(8):1214-21; Rasmussen TB et al. Hum Mutat. 2013;34(5):697-705; van Lint FHM et al. Circ Genom Precis Med. 2019 08;12(8):e002467; Lao N et al. Eur Heart J Case Rep. 2021 Jun;5(6)). This variant was observed to co-segregate with ARVC in three siblings in one family; however, two relatives with this variant exhibited either absent or limited phenotype, suggesting reduced penetrance (Lahtinen AM et al. Heart Rhythm. 2011;8(8):1214-21). This variant has also been detected in cohorts without known ARVC; however, clinical details were limited (Abicht A et al. Cardiovasc Diagn Ther. 2021 Apr;11(2):637-649; Lacaze P et al. NPJ Genom Med. 2021 Jun;6(1):51). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000496000	SCV000584087	likely pathogenic	Dilated cardiomyopathy 1BB	2015-10-08	criteria provided, single submitter	research
Invitae	RCV000560883	SCV000641980	pathogenic	Arrhythmogenic right ventricular dysplasia 10	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu1020Alafs*18) in the DSG2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 99 amino acid(s) of the DSG2 protein. This variant is present in population databases (rs746854378, gnomAD 0.009%). This premature translational stop signal has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 20864495, 21397041, 23381804). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 199827). This variant disrupts a region of the DSG2 protein in which other variant(s) (p.Glu1083Ser) have been observed in individuals with DSG2-related conditions (PMID: 21636032). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852476	SCV000995170	likely pathogenic	Cardiomyopathy	2018-11-28	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000560883	SCV001190277	pathogenic	Arrhythmogenic right ventricular dysplasia 10	2019-07-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000852476	SCV001343088	uncertain significance	Cardiomyopathy	2023-08-15	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 15 of the DSG2 gene, creating a frameshift in the last exon. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a protein product containing altered C-terminal sequence. To our knowledge, functional studies have not been reported for this variant. This variant has been identified in eight unrelated individuals affected with arrhythmogenic cardiomyopathy (PMID: 21397041, 20864495, 23381804, 33821670, 34263121, 36431211) and has been reported to segregate with disease in one of the families (PMID: 21397041). This variant has also been observed in individuals affected with conduction defect (PMID: 21397041), hypertrophic cardiomyopathy (PMID: 34500006), or dilated cardiomyopathy (PMID: 36129056), and in unaffected family members (PMID 21397041) as well as in individuals without history of cardiovascular events (PMID: 33968641, 34135346). Furthermore, the variant has been reported in compound heterozygous state with another DSG2 variant in three individual affected with arrhythmogenic cardiomyopathy (PMID: 37418234). This variant has been identified in 9/249404 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, the available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000560883	SCV001434980	likely pathogenic	Arrhythmogenic right ventricular dysplasia 10	2019-10-31	criteria provided, single submitter	clinical testing	The c.3059_3062delAGAG (p.Glu1020Alafs*18) variant in the DSG2 gene is predicted to introduce a premature translational termination codon, expecting to disrupt the last 99 amino acids of the DSG2 protein. This variant has been reported in individuals and a family affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 20864495, 21397041, 23381804). This variant is present in population databases at low frequency (gnomAD 0.003609%). Therefore, this c.3059_3062delAGAG (p.Glu1020Alafs*18) variant in the DSG2 gene is classified as likely pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV002223806	SCV002502934	uncertain significance	not provided	2021-11-02	criteria provided, single submitter	clinical testing
Mendelics	RCV000560883	SCV002519584	pathogenic	Arrhythmogenic right ventricular dysplasia 10	2022-05-04	criteria provided, single submitter	clinical testing