Submissions for variant NM_024422.6(DSC2):c.2582_2585dup (p.Gly863fs)

dbSNP: rs780970079

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000818101	SCV000958696	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2022-05-17	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change creates a premature translational stop signal (p.Gly863Lysfs*13) in the DSC2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 39 amino acid(s) of the DSC2 protein. This variant is present in population databases (rs780970079, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 25616645). ClinVar contains an entry for this variant (Variation ID: 199787). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170828	SCV001333447	uncertain significance	Cardiomyopathy	2018-06-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001170828	SCV001351593	uncertain significance	Cardiomyopathy	2023-05-10	criteria provided, single submitter	clinical testing	This variant duplicates 4 nucleotides in exon 16 of of the DSC2 gene, creating a frameshift in the last exon. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a protein product containing altered C-terminal sequence. To our knowledge, functional assays have not been performed for this variant. This variant has been observed in individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 25616645, 28588093). This variant has also been identified in 3/251090 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.
Ambry Genetics	RCV002426868	SCV002742615	uncertain significance	Cardiovascular phenotype	2023-11-27	criteria provided, single submitter	clinical testing	The c.2582_2585dupGAAG variant, located in coding exon 16 of the DSC2 gene, results from a duplication of GAAG at nucleotide position 2582, causing a translational frameshift with a predicted alternate stop codon (p.G863Kfs*13). This alteration occurs at the 3' terminus of theDSC2 gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 3% of the protein. The exact functional effect of this alteration is unknown. This alteration has been reported in an arrhythmogenic right ventricular cardiomyopathy (ARVC) cohort; however, clinical details were limited (Groeneweg JA et al. Circ Cardiovasc Genet, 2015 Jun;8:437-46). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV000818101	SCV002785797	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2021-09-08	criteria provided, single submitter	clinical testing