Submissions for variant NM_001943.5(DSG2):c.1280+4AG[3]

dbSNP: rs876657791

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000223330	SCV000271712	uncertain significance	not specified	2015-04-13	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The c.1280+4AG[3] ( also reported as c.1280+4_1280+5delAG) variant in DSG2 has not been previously r eported in individuals with cardiomyopathy, but has been identified in 0.2% (19/ 8616) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http: //exac.broadinstitute.org). This variant results in a deletion of one dinucleoti de repeat in the 5' splice region. Computational tools do not suggest an impact to splicing. However, this information is not predictive enough to rule out path ogenicity. In summary, while the clinical significance of the c.1280+4AG[3] vari ant is uncertain, its frequency suggests that it is more likely to be benign.
Illumina Laboratory Services, Illumina	RCV000377305	SCV000408226	uncertain significance	Dilated Cardiomyopathy, Dominant	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000266431	SCV000408227	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000223330	SCV000570740	likely benign	not specified	2016-06-24	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590706	SCV000697881	likely benign	not provided	2017-03-06	criteria provided, single submitter	clinical testing	Variant summary: The DSG2 c.1280+10_1280+11delAG variant involves the alteration of an intronic nucleotide, which 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 19/120602 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.002206 (19/8612). This frequency is about 221 times the estimated maximal expected allele frequency of a pathogenic DSG2 variant (0.00001), suggesting this is likely a benign polymorphism found primarily in population(s) of East Asian origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance, without additional information to perform an independent evaluation. Therefore, the variant of interest has been classified as "likely benign."
Invitae	RCV001078612	SCV000764004	likely benign	Arrhythmogenic right ventricular dysplasia 10	2024-01-09	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001184745	SCV001350801	benign	Cardiomyopathy	2018-12-03	criteria provided, single submitter	clinical testing
Phosphorus, Inc.	RCV000223330	SCV002073404	likely benign	not specified	2022-01-19	criteria provided, single submitter	clinical testing	This deletion variant is located 10bp away from the canonical splice-site in intron 9 of the DSG2 gene (transcript: NM_001943.3). This variant has an entry in ClinVar (228628) NM_001943.5(DSG2):c.1280+4AG[3]. This variant occurred in gnomAD with a total MAF of 0.0175% and the highest MAF of 0.2494% in the East Asian population. This position is not conserved. In silico splicing algorithms predicted that this variant will not have an impact on splicing (not found in scSNV). The variant has not occurred in the literature in association with disease. Considering that the variant has a relatively high frequency in the population, it has been classified as Likely Benign.
PreventionGenetics, part of Exact Sciences	RCV003947717	SCV004764476	likely benign	DSG2-related condition	2020-10-19	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).