Submissions for variant NM_001943.5(DSG2):c.216+3A>C

gnomAD frequency: 0.00003  dbSNP: rs774208829

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181201	SCV000233479	uncertain significance	not provided	2019-04-11	criteria provided, single submitter	clinical testing	In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Invitae	RCV001044064	SCV001207838	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2023-08-11	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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: 199797). This variant has not been reported in the literature in individuals affected with DSG2-related conditions. This variant is present in population databases (rs774208829, gnomAD 0.02%). This sequence change falls in intron 3 of the DSG2 gene. It does not directly change the encoded amino acid sequence of the DSG2 protein. It affects a nucleotide within the consensus splice site.
Color Diagnostics, LLC DBA Color Health	RCV001189658	SCV001356989	uncertain significance	Cardiomyopathy	2022-06-07	criteria provided, single submitter	clinical testing	This variant causes an A>C nucleotide substitution at the +3 position of intron 3 of the DSG2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/31396 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
Ambry Genetics	RCV002426869	SCV002731294	uncertain significance	Cardiovascular phenotype	2021-08-27	criteria provided, single submitter	clinical testing	The c.216+3A>C intronic variant results from an A to C substitution 3 nucleotides after coding exon 3 in the DSG2 gene. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002492799	SCV002777358	uncertain significance	Arrhythmogenic right ventricular dysplasia 10; Dilated cardiomyopathy 1BB	2021-08-31	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996611	SCV004826193	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2023-11-28	criteria provided, single submitter	clinical testing