ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.2620del (p.Thr874fs)

dbSNP: rs755243947
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001036046 SCV001199392 pathogenic Arrhythmogenic right ventricular dysplasia 10 2023-10-12 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Thr874Leufs*29) in the DSG2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 245 amino acid(s) of the DSG2 protein. This variant is present in population databases (rs755243947, gnomAD 0.0009%). 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: 835215). 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.
CeGaT Center for Human Genetics Tuebingen RCV002264145 SCV002546003 likely pathogenic not provided 2022-12-01 criteria provided, single submitter clinical testing DSG2: PVS1:Strong, PM2
Ambry Genetics RCV002427483 SCV002744618 likely pathogenic Cardiovascular phenotype 2019-07-16 criteria provided, single submitter clinical testing The c.2620delA variant, located in coding exon 15 of the DSG2 gene, results from a deletion of one nucleotide at nucleotide position 2620, causing a translational frameshift with a predicted alternate stop codon (p.T874Lfs*29). Premature stop codons are typically deleterious in nature; however, since this stop codon occurs in the last exon, it is not expected to trigger nonsense-mediated mRNA decay and impacts only the last 247 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time; however, the C-terminal region of DSG2 has been implicated in protein stabilization at the cell surface and in tail-tail interactions (Chen J et al. J Cell Biol. 2012;199(4):699-711). In addition, frameshift and premature truncating alterations beyond this position (e.g., c.3059_3062delAGAG, p.E1020Afs*18) have been reported in association with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) (Christensen AH et al. J Med Genet. 2010;47(11):736-44). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx RCV002264145 SCV005080969 uncertain significance not provided 2024-03-12 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in abnormal protein length as the last 245 amino acids are replaced with 28 different amino acids

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