Submissions for variant NM_024422.6(DSC2):c.1664-1G>C

dbSNP: rs776877367

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001067340	SCV001232397	likely pathogenic	Arrhythmogenic right ventricular dysplasia 11	2019-04-19	criteria provided, single submitter	clinical testing	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. 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: 23911551). This variant is present in population databases (rs776877367, ExAC 0.002%). This variant has not been reported in the literature in individuals with DSC2-related conditions. 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. This sequence change affects an acceptor splice site in intron 11 of the DSC2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Color Diagnostics, LLC DBA Color Health	RCV001525560	SCV001735716	uncertain significance	Cardiomyopathy	2020-12-15	criteria provided, single submitter	clinical testing	This variant causes a G to C nucleotide substitution at the -1 position of intron 11 splice acceptor site of the DSC2 gene. Splice prediction tools suggest that this variant may have a significant impact on splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/247366 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, clinical relevance of loss-of-function DSC2 truncation and splice variants in autosomal dominant arrhythmogenic cardiomyopathy is not yet clearly established. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV002286808	SCV002577002	likely pathogenic	not provided	2022-03-24	criteria provided, single submitter	clinical testing	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); Has not been previously published in association with a DSC2-related disorder to our knowledge; This variant is associated with the following publications: (PMID: 33087929, 31638835)