ClinVar Miner

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

dbSNP: rs727502990
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Total submissions: 3
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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to result in a truncated prot ein have been reported in individuals with ARVC (Human Gene Mutation Database, L MM unpublished data).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.

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