ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.1487dup (p.Cys496fs) (rs730880347)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000155624 SCV000205332 uncertain significance not specified 2017-12-07 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Cys496fs variant in DSG2 has been identified by our laboratory in 1 Caucasian individual with possible ARVC including biventricular dilation and VT; however this individ ual also carried a likely pathogenic variant in TTN. The p.Cys496fs variant was absent from large population studies. This variant is predicted to cause a frame shift, which alters the protein?s amino acid sequence beginning at position 496 and leads to a premature termination codon 40 amino acids downstream. This alter ation is then predicted to lead to a truncated or absent protein. Frameshift and other loss of function variants in DSG2 gene have been reported in individuals with ARVC. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Cys496fs variant is uncertain.
Invitae RCV000642310 SCV000763979 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 10 2020-04-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Cys496Trpfs*40) in the DSG2 gene. It is expected to result in an absent or disrupted protein product. 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 disease. Loss-of-function variants in DSG2 are known to be pathogenic (PMID: 23381804, 23911551). For these reasons, this variant has been classified as Pathogenic.

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