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

gnomAD frequency: 0.00001  dbSNP: rs397516709

Total submissions: 7

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with clinical features of arrhythmogenic right ventricular cardiomyopathy (ARVC; Fressart 2010 , Tan 2010, LMM unpublished data).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	2023-01-10	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs397516709, gnomAD 0.002%). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 44321). Disruption of this splice site has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 2040044, 20857253). 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).
Ambry Genetics	RCV000241644	SCV000320191	pathogenic	Cardiovascular phenotype	2020-06-15	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 of the DSG2 gene. This alteration has been previously reported in several patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), sometimes in conjunction with other ARVC variants (Fressart V, Europace 2010 Jun; 12(6):861-8; Tan BY, J Cardiovasc Transl Res 2010 Dec; 3(6):663-73). This variant has also been detected in a sudden infant death syndrome cohort (Tester DJ et al. J. Am. Coll. Cardiol., 2018 03;71:1217-1227). 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	2023-12-07	criteria provided, single submitter	clinical testing