ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.216+3A>C (rs774208829)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181201 SCV000233479 uncertain significance not provided 2016-12-20 criteria provided, single submitter clinical testing The c.216+3 A>C variant in the DSG2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. In silico analysis using several splice algorithms predicts that c.216+3 A>C significantly reduces the efficiency or completely abolishes the natural splice donor site in intron 3. Additionally, the c.216+3 A>C was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Other splice site mutations have been reported in the DSG2 gene in association with cardiomyopathy. However, another splice site variant in the same intron (c.216+2 T>C) has been reported as an unclassified variant (Van der Zwaag et al., 2009). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in ARVC panel(s).
Invitae RCV001044064 SCV001207838 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2020-10-21 criteria provided, single submitter clinical testing 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, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with DSG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 199797). Nucleotide substitutions within 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, but this prediction has not been confirmed by published transcriptional studies. 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.
Color Health, Inc RCV001189658 SCV001356989 uncertain significance Cardiomyopathy 2019-08-21 criteria provided, single submitter clinical testing

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