ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.2125+1del (rs794728072)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181172 SCV000233449 likely pathogenic not provided 2017-09-18 criteria provided, single submitter clinical testing The c.2125+1delG splice site variant in the DSC2 gene has not been published previously, to our knowledge, other canonical splice site variants which are known to be pathogenic have been reported in DSC2 in association with arrhythmogenic right ventricular cardiomyopathy (Stenson et al., 2014). Based on the ACMG recommendations, c.2125+1delG is interpreted as an expected pathogenic sequence change.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000611988 SCV000731717 uncertain significance not specified 2017-11-21 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The c.2125+1del G variant in DSC2 has been reported in 1 individual with ARVC (Venlet 2017) and was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 199778). The c.2125+1delG variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause alt ered splicing leading to an abnormal or absent protein. Splice site and other lo ss of function variants in DSC2 have been reported in individuals with ARVC. In summary, while there is some suspicion for a pathogenic role, the clinical signi ficance of the c.2152+1delG variant is uncertain.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000601575 SCV000743492 pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 11 2014-10-08 criteria provided, single submitter clinical testing
Invitae RCV000601575 SCV000820151 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 11 2018-09-19 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 13 of the DSC2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with ventricular tachycardia (PMID: 28153106). ClinVar contains an entry for this variant (Variation ID: 199778). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DSC2 are known to be pathogenic (PMID: 18957847, 23863954, 23911551). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000601575 SCV000839948 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 11 2017-01-18 criteria provided, single submitter clinical testing This c.2125+1del variant has been reported in dbSNP (rs794728072) and ClinVar (RCV000181172.1). The frequency of this variant is unknown and this variant has not previously been observed in our patient cohort. This c.2125+1del variant affects the invariant acceptor splice site of intron 13 of the DSC2 gene. While not validated for clinical use, the computer-based algorithms predict this variant to disrupt the invariant donor splicing site. Loss of function variants including splicing site variants are disease-causing for this disorder. It is thus interpreted as a pathogenic variant.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV001256686 SCV001433080 likely pathogenic Dilated cardiomyopathy 1A 2019-03-14 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000601575 SCV000733775 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy, type 11 no assertion criteria provided clinical testing

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