Submissions for variant NM_001943.5(DSG2):c.2875_2876del (p.Gln959fs)

dbSNP: rs727502990

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150546	SCV000197773	uncertain significance	not specified	2014-08-27	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The Gln959fs va riant in DSG2 has not been previously reported in individuals with cardiomyopath y. Data from large population studies is insufficient to assess the frequency of this variant. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 959 and leads to a prematur e termination codon 22 amino acids downstream. This termination codon occurs wit hin the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Variants suspected to result in a truncated prot ein have been reported in individuals with ARVC (Human Gene Mutation Database, L MM unpublished data). In summary, while there is some suspicion for a pathogenic role, the clinical significance of the Gln959fs variant is uncertain.
Color Diagnostics, LLC DBA Color Health	RCV001188344	SCV001355381	uncertain significance	Cardiomyopathy	2023-03-15	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 15 of the DSG2 gene, creating a frameshift and premature translation stop signal in the last exon. To our knowledge, functional studies have not been reported for this variant nor has it been reported in individuals affected with DSG2-related disorders in the literature. This variant has not been identified 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.
Invitae	RCV001850043	SCV002235979	pathogenic	Arrhythmogenic right ventricular dysplasia 10	2023-12-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln959Glufs*22) in the DSG2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 160 amino acid(s) of the DSG2 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DSG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 163222). 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. For these reasons, this variant has been classified as Pathogenic.
All of Us Research Program, National Institutes of Health	RCV003998193	SCV004821846	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2023-11-02	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This variant deletes 2 nucleotides in last exon 15 of the DSG2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively.