Submissions for variant NM_001943.5(DSG2):c.523+2T>C

gnomAD frequency: 0.00001  dbSNP: rs397516709

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037309	SCV000060966	likely pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2018-02-21	criteria provided, single submitter	clinical testing	The c.523+2T>C variant in DSG2 has been reported in 6 individuals with clinical features of arrhythmogenic right ventricular cardiomyopathy (ARVC; Fressart 2010 , Tan 2010, LMM unpublished data). This variant has been identified in 2/105830 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.b roadinstitute.org; dbSNP rs397516709) and reported in ClinVar (Variation ID 4432 1). c.523+2T>C variant occurs in the invariant region (+/- 1,2) of the splice co nsensus sequence and is predicted to cause altered splicing leading to an abnorm al or absent protein. Heterozygous loss of function of the DSG2 gene has been im plicated in ARVC. In summary, although additional studies are required to fully establish its clinical significance, the c.523+2T>C variant is likely pathogenic . ACMG/AMP Criteria applied: PM2; PVS1_Moderate; PS4_Moderate.
GeneDx	RCV000181206	SCV000233484	pathogenic	not provided	2024-08-05	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20400443, 26314686, 25525159, 20857253, 23671136, 23889974, 23810894, 28588093, 28471438, 25820315, 30790397, 30122538, 29544605, 31386562, 31402444, 31589614, 33232181, 33238575)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000232524	SCV000287244	pathogenic	Arrhythmogenic right ventricular dysplasia 10	2024-08-19	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 5 of the DSG2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DSG2 are known to be pathogenic (PMID: 17105751, 31386562). This variant is present in population databases (rs397516709, gnomAD 0.002%). Disruption of this splice site has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 2040044, 20857253). ClinVar contains an entry for this variant (Variation ID: 44321). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000241644	SCV000320191	pathogenic	Cardiovascular phenotype	2024-10-10	criteria provided, single submitter	clinical testing	The c.523+2T>C intronic pathogenic mutation results from a T to C substitution two nucleotides after coding exon 5 in the DSG2 gene. This variant was reported in multiple individuals with features consistent with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Fressart V et al. Europace, 2010 Jun;12:861-8; Tan BY et al. J Cardiovasc Transl Res, 2010 Dec;3:663-73; Bhonsale A et al. Circ Arrhythm Electrophysiol, 2013 Jun;6:569-78; te Riele AS et al. J Am Coll Cardiol, 2013 Nov;62:1761-9; Groeneweg JA et al. Circ Cardiovasc Genet, 2015 Jun;8:437-46; Xiong HY et al. Science, 2015 Jan;347:1254806; Tester DJ et al. J Am Coll Cardiol, 2018 Mar;71:1217-1227). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
AiLife Diagnostics, AiLife Diagnostics	RCV000181206	SCV002503398	pathogenic	not provided	2021-07-12	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002477091	SCV002777468	likely pathogenic	Arrhythmogenic right ventricular dysplasia 10; Dilated cardiomyopathy 1BB	2021-09-18	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000037309	SCV004830338	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2024-08-06	criteria provided, single submitter	clinical testing	This variant causes a T>C nucleotide substitution at the +2 position of intron 5 of the DSG2 gene. Splice prediction tools suggest that this variant may have a significant impact on splicing. To our knowledge, RNA studies have not been reported for this variant. This variant has been reported in at least ten individuals affected with arrhythmogenic right ventricular cardiomyopathy including one homozygous individual (PMID: 2040044, 28588093, 30790397, 33238575, 37418234, ClinVar SCV000060966.5, SCV000233484.13) and in an infant affected with sudden death syndrome (PMID: 29544605). This variant has also been observed in 7 unaffected adults, 2 children without known cardiac disease, and in 3 additional individuals with unknown health history (PMID: 33684294; ClinVar SCV000060966.5, SCV000233484.13, SCV000320191.6). This variant has been identified in 2/236788 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, clinical significance of loss-of-function DSG2 variants in autosomal dominant arrhythmogenic right ventricular cardiomyopathy is not yet clearly established. 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.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000232524	SCV005395954	likely pathogenic	Arrhythmogenic right ventricular dysplasia 10	2024-05-29	criteria provided, single submitter	clinical testing