Submissions for variant NM_001943.5(DSG2):c.2955del (p.Val986fs)

dbSNP: rs1064794709

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485291	SCV000569777	uncertain significance	not provided	2018-08-13	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 29790872)
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000496079	SCV000584086	pathogenic	Dilated cardiomyopathy 1BB	2015-09-04	criteria provided, single submitter	research
Ambry Genetics	RCV002436539	SCV002750175	likely pathogenic	Cardiovascular phenotype	2024-05-17	criteria provided, single submitter	clinical testing	The c.2955delT variant, located in coding exon 15 of the DSG2 gene, results from a deletion of one nucleotide at nucleotide position 2955, causing a translational frameshift with a predicted alternate stop codon (p.V986Wfs*6). This alteration occurs at the 3' terminus of theDSG2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 11% of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV002525851	SCV003473206	pathogenic	Arrhythmogenic right ventricular dysplasia 10	2022-12-11	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: 420800). This premature translational stop signal has been observed in individual(s) with postpartum cardiomyopathy (PMID: 29790872). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Val986Trpfs*6) in the DSG2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 133 amino acid(s) of the DSG2 protein.
All of Us Research Program, National Institutes of Health	RCV004003335	SCV004828260	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2023-05-30	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. 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, this variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/248354 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.