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

dbSNP: rs794728072

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181172	SCV000233449	likely pathogenic	not provided	2023-10-31	criteria provided, single submitter	clinical testing	While this variant has been reported in studies exploring ARVC, these individuals either did not manifest symptoms of disease or it is unclear whether the individual(s) harboring this variant were clinically diagnosed with ARVC (PMID: 31638835, 28153106); Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31447099, 28153106, 33662488, 31638835)
Laboratory for Molecular Medicine, Mass General Brigham 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.
Invitae	RCV000601575	SCV000820151	likely pathogenic	Arrhythmogenic right ventricular dysplasia 11	2023-10-27	criteria provided, single submitter	clinical testing	This sequence change affects a splice site in intron 13 of the DSC2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DSC2 are known to be pathogenic (PMID: 23911551). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with dilated cardiomyopathy and/or ventricular tachycardia (PMID: 28153106, 31931689, 33662488). ClinVar contains an entry for this variant (Variation ID: 199778). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 dysplasia 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
Institute of Human Genetics, University of Leipzig Medical Center	RCV000601575	SCV002026386	likely pathogenic	Arrhythmogenic right ventricular dysplasia 11	2021-11-16	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PVS1, PS4_MOD, PM2_SUP
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000601575	SCV000733775	likely pathogenic	Arrhythmogenic right ventricular dysplasia 11		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000181172	SCV000743492	likely pathogenic	not provided		no assertion criteria provided	clinical testing