Submissions for variant NM_001943.5(DSG2):c.2257del (p.Ala753fs)

dbSNP: rs1567933176

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000706687	SCV000835754	pathogenic	Arrhythmogenic right ventricular dysplasia 10	2024-07-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ala753Leufs*15) in the DSG2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 366 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: 582579). 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.
Fulgent Genetics, Fulgent Genetics	RCV002493249	SCV002791959	likely pathogenic	Arrhythmogenic right ventricular dysplasia 10; Dilated cardiomyopathy 1BB	2021-09-18	criteria provided, single submitter	clinical testing
Clinical Genomics Laboratory, Washington University in St. Louis	RCV000706687	SCV005685155	likely pathogenic	Arrhythmogenic right ventricular dysplasia 10	2024-06-08	criteria provided, single submitter	clinical testing	The DSG2 c.2257del (p.Ala753Leufs*15) variant, to our knowledge, has not been reported in the medical literature. This variant has been reported in the ClinVar database as a pathogenic variant by one submitter and as likely pathogenic by one submitter. This variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant causes a frameshift by deleting one nucleotide, leading to a premature termination codon, which is predicted to lead to nonsense mediated decay. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic.