Submissions for variant NM_001943.5(DSG2):c.2817del (p.Tyr940fs)

dbSNP: rs1567934773

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000699399	SCV000828106	pathogenic	Arrhythmogenic right ventricular dysplasia 10	2022-07-08	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with DSG2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr940Metfs*12) in the DSG2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 179 amino acid(s) of the DSG2 protein. ClinVar contains an entry for this variant (Variation ID: 576810). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the DSG2 protein in which other variant(s) (p.Glu1020Alafs*18) have been determined to be pathogenic (PMID: 20864495, 21397041, 23381804). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing.
Color Diagnostics, LLC DBA Color Health	RCV001192101	SCV001360076	uncertain significance	Cardiomyopathy	2019-12-04	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 15 of the DSG2 gene, creating a frameshift and premature translation stop signal in the last exon. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Clinical significance of loss-of-function truncation variants in the DSG2 gene is not clearly established. 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.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000699399	SCV001434979	likely pathogenic	Arrhythmogenic right ventricular dysplasia 10	2018-08-06	criteria provided, single submitter	clinical testing	The frameshift variant, c.2817delC (p.Tyr940Metfs*12) in the DSG2 gene is predicted to introduce a premature translation termination codon. It has not been seen in the general population according to the gnomAD database. Loss of function could be the mechanism for DSG2 protein (PMID 23911551, 23381804). Therefore, this variant is classified as likely pathogenic.