Submissions for variant NM_001943.5(DSG2):c.1487dup (p.Cys496fs)

dbSNP: rs730880347

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155624	SCV000205332	uncertain significance	not specified	2017-12-07	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Cys496fs variant in DSG2 has been identified by our laboratory in 1 Caucasian individual with possible ARVC including biventricular dilation and VT; however this individ ual also carried a likely pathogenic variant in TTN. The p.Cys496fs variant was absent from large population studies. This variant is predicted to cause a frame shift, which alters the protein?s amino acid sequence beginning at position 496 and leads to a premature termination codon 40 amino acids downstream. This alter ation is then predicted to lead to a truncated or absent protein. Frameshift and other loss of function variants in DSG2 gene have been reported in individuals with ARVC. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Cys496fs variant is uncertain.
Invitae	RCV000642310	SCV000763979	pathogenic	Arrhythmogenic right ventricular dysplasia 10	2021-04-04	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in DSG2 are known to be pathogenic (PMID: 23381804, 23911551). This variant has not been reported in the literature in individuals with DSG2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Cys496Trpfs*40) in the DSG2 gene. It is expected to result in an absent or disrupted protein product.
GeneDx	RCV001657888	SCV001874875	likely pathogenic	not provided	2023-10-09	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published in association with DSG2-related disorders to our knowledge; This variant is associated with the following publications: (PMID: 31638835)
Ambry Genetics	RCV002390355	SCV002702654	pathogenic	Cardiovascular phenotype	2022-12-07	criteria provided, single submitter	clinical testing	The c.1487dupG pathogenic mutation, located in coding exon 11 of the DSG2 gene, results from a duplication of G at nucleotide position 1487, causing a translational frameshift with a predicted alternate stop codon (p.C496Wfs*40). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.