Submissions for variant NM_001943.5(DSG2):c.3052dup (p.Glu1018fs)

dbSNP: rs1261674855

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001380806	SCV001578986	pathogenic	Arrhythmogenic right ventricular dysplasia 10	2022-11-29	criteria provided, single submitter	clinical testing	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. ClinVar contains an entry for this variant (Variation ID: 1069061). This variant has not been reported in the literature in individuals affected with DSG2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Glu1018Glyfs*20) in the DSG2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 101 amino acid(s) of the DSG2 protein.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282534	SCV002572293	likely pathogenic	Cardiomyopathy	2022-08-24	criteria provided, single submitter	clinical testing	Variant summary: DSG2 c.3052dupG (p.Glu1018GlyfsX20), located in the last exon (stop codon spans c.3355 to c.3357 at position 1119), results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 8e-06 in 249390 control chromosomes (gnomAD). To our knowledge, no occurrence of c.3052dupG in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV001380806	SCV003835832	likely pathogenic	Arrhythmogenic right ventricular dysplasia 10	2022-10-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004037645	SCV005017997	uncertain significance	Cardiovascular phenotype	2023-10-24	criteria provided, single submitter	clinical testing	The c.3052dupG variant, located in coding exon 15 of the DSG2 gene, results from a duplication of G at nucleotide position 3052, causing a translational frameshift with a predicted alternate stop codon (p.E1018Gfs*20). This alteration occurs at the 3' terminus of theDSG2 gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 9% of the protein. The exact functional effect of this alteration is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.