Submissions for variant NM_024422.6(DSC2):c.2251-5T>G

gnomAD frequency: 0.00009  dbSNP: rs374262463

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001176599	SCV001340627	uncertain significance	Cardiomyopathy	2023-02-28	criteria provided, single submitter	clinical testing	This variant causes a T to G nucleotide substitution at the -5 position of intron 14 of the DSC2 gene. Computational splicing tools and conservation analyses are inconclusive regarding the impact of this variant on RNA 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 7/281344 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae	RCV001248696	SCV001422202	likely benign	Arrhythmogenic right ventricular dysplasia 11	2024-01-24	criteria provided, single submitter	clinical testing
GeneDx	RCV001571072	SCV001795473	uncertain significance	not provided	2019-04-25	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.
Ambry Genetics	RCV002444874	SCV002735176	likely benign	Cardiovascular phenotype	2022-11-15	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
PreventionGenetics, part of Exact Sciences	RCV003919897	SCV004731206	likely benign	DSC2-related condition	2023-10-26	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223919	SCV000280077	uncertain significance	not specified	2014-10-29	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Given the lack of case data and the frequency in the patient's ancestral group, we consider this variant a variant of uncertain significance, probably benign. We could find no reports of the variant online or in the ARVD mutation database (http://www.arvcdatabase.info/Default.aspx). The variant is predicted to damage the canonical splice acceptor site. The variant was reported online in 4 of 59812 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of September 16, 2015). Specifically, the variant was observed in 4 of 4907 African individuals (MAF 0.04%). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.