Submissions for variant NM_024422.6(DSC2):c.2623C>T (p.Arg875Ter)

gnomAD frequency: 0.00001  dbSNP: rs727504823

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156162	SCV000205878	uncertain significance	not specified	2013-11-08	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The Arg875X var iant in DSC2 has not been previously reported in individuals with cardiomyopathy or in large population studies. This nonsense variant leads to a premature term ination codon at position 875. This variant is located in the terminal exon, whe re nonsense mediated decay is unlikely, leading to a truncated protein lacking l ast 27 amino acids. One study reports a similar variant further upstream in the same exon that was shown to interfere with normal protein function (Asp859fsX4, Gehmlich 2011). On the other hand, a variant downstream (Ala897fs) is thought to be benign. In summary, is unclear whether this truncation will impact protein f unction and additional studies are required to fully establish its clinical sign ificance.
GeneDx	RCV000767139	SCV000577103	uncertain significance	not provided	2017-04-11	criteria provided, single submitter	clinical testing	The R875X variant of uncertain significance in the DSC2 gene has not been published as pathogenic or been reported as benign to our knowledge. R875X, located in the last exon of the DSC2 gene, is predicted to cause loss of normal protein function via truncation of the final 27 amino acids of the protein product. This variant is not observed at a significant frequency in the Exome Aggregation Consortium (Lek et al., 2016). Other nonsense and frameshift variants in the DSC2 gene have been reported in Human Gene Mutation Database in association with ARVC (Stenson et al., 2014). Gerull et al. (2013) identified a homozygous nonsense variant (Q554X) associated with ARVC in a Canadian Hutterite population. This nonsense variant lead to desmocollin-2 protein truncation, as determined by immunofluorescence imaging of endomyocardial biopsy specimens. The truncated protein was stable and localized at or near the intercalated discs. However, a different truncation variant that removes the C-terminal five amino acids (c.2686_2687dupGA) has been reported to be a polymorphism based on presence in controls (De Bortoli et al,. 2010).
Invitae	RCV000538816	SCV000645012	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2023-12-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg875*) in the DSC2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 27 amino acid(s) of the DSC2 protein. This variant is present in population databases (rs727504823, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with DSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 179373). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
Color Diagnostics, LLC DBA Color Health	RCV001184541	SCV001350549	uncertain significance	Cardiomyopathy	2023-02-08	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 16 of the DSC2 gene, creating a premature translation stop signal in the last exon. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. To our knowledge, this variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 9/282604 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	RCV002426754	SCV002743110	uncertain significance	Cardiovascular phenotype	2019-05-23	criteria provided, single submitter	clinical testing	The p.R875* variant (also known as c.2623C>T), located in coding exon 16 of the DSC2 gene, results from a C to T substitution at nucleotide position 2623. This changes the amino acid from an arginine to a stop codon within coding exon 16. Premature stop codons are typically deleterious in nature, however, this stop codon occurs at the 3' terminus of DSC2, is not expected to trigger nonsense-mediated mRNA decay, and removes only the last 27 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time.
Fulgent Genetics, Fulgent Genetics	RCV000538816	SCV002793224	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2021-11-10	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000157176	SCV000206900	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2014-11-25	no assertion criteria provided	clinical testing