ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.2623C>T (p.Arg875Ter) (rs727504823)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000157176 SCV000206900 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2014-11-25 no assertion criteria provided clinical testing
GeneDx RCV000767139 SCV000577103 uncertain significance not provided 2017-04-11 criteria provided, single submitter clinical testing The R875X variant of uncertain significance in the DSC2 gene has not been published as pathogenic or been reported as benign to our knowledge. R875X, located in the last exon of the DSC2 gene, is predicted to cause loss of normal protein function via truncation of the final 27 amino acids of the protein product. This variant is not observed at a significant frequency in the Exome Aggregation Consortium (Lek et al., 2016). Other nonsense and frameshift variants in the DSC2 gene have been reported in Human Gene Mutation Database in association with ARVC (Stenson et al., 2014). Gerull et al. (2013) identified a homozygous nonsense variant (Q554X) associated with ARVC in a Canadian Hutterite population. This nonsense variant lead to desmocollin-2 protein truncation, as determined by immunofluorescence imaging of endomyocardial biopsy specimens. The truncated protein was stable and localized at or near the intercalated discs. However, a different truncation variant that removes the C-terminal five amino acids (c.2686_2687dupGA) has been reported to be a polymorphism based on presence in controls (De Bortoli et al,. 2010).
Invitae RCV000538816 SCV000645012 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 11 2018-02-01 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the DSC2 gene (p.Arg875*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 27 amino acids of the DSC2 protein. This variant is present in population databases (rs727504823, ExAC 0.001%). This variant has not been reported in the literature in individuals with DSC2-related disease. ClinVar contains an entry for this variant (Variation ID: 179373). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acids is currently unknown. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000156162 SCV000205878 uncertain significance not specified 2013-11-08 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The Arg875X var iant in DSC2 has not been previously reported in individuals with cardiomyopathy or in large population studies. This nonsense variant leads to a premature term ination codon at position 875. This variant is located in the terminal exon, whe re nonsense mediated decay is unlikely, leading to a truncated protein lacking l ast 27 amino acids. One study reports a similar variant further upstream in the same exon that was shown to interfere with normal protein function (Asp859fsX4, Gehmlich 2011). On the other hand, a variant downstream (Ala897fs) is thought to be benign. In summary, is unclear whether this truncation will impact protein f unction and additional studies are required to fully establish its clinical sign ificance.

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