Submissions for variant NM_001943.5(DSG2):c.3293C>G (p.Ser1098Cys)

gnomAD frequency: 0.00004  dbSNP: rs2848673

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171907	SCV000050909	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000214180	SCV000271718	uncertain significance	not specified	2015-03-11	criteria provided, single submitter	clinical testing	The p.Ser1098Cys variant in DSG2 has been reported at least 1 individual with AR VC or suspected ARVC (den Haan 2009), but has also been identified in 4/66638 Eu ropean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadi nstitute.org; dbSNP rs2848673). Serine at position 1098 is not conserved in evol ution and 2 mammalian species (bats) carry a cystine (Cys) at this position, rai sing the possibility that this change is tolerated. In summary, the clinical sig nificance of the p.Ser1098Cys variant is uncertain.
Color Diagnostics, LLC DBA Color Health	RCV001179560	SCV001344252	uncertain significance	Cardiomyopathy	2023-02-08	criteria provided, single submitter	clinical testing	This missense variant replaces serine with cysteine at codon 1098 of the DSG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 20031617). This variant has been identified in 8/249178 chromosomes 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	RCV001223258	SCV001395397	likely benign	Arrhythmogenic right ventricular dysplasia 10	2023-11-11	criteria provided, single submitter	clinical testing
GeneDx	RCV000171907	SCV002002800	uncertain significance	not provided	2021-03-26	criteria provided, single submitter	clinical testing	Reported in a study that explored ARVC variants in North Americans, however, the authors excluded the S1098C variant, presumably due to its presence in control populations (denHaan et al., 2009); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance by several clinical laboratories (ClinVar Variant ID#191633; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 20031617)
Ambry Genetics	RCV002453592	SCV002611961	uncertain significance	Cardiovascular phenotype	2021-07-23	criteria provided, single submitter	clinical testing	The p.S1098C variant (also known as c.3293C>G), located in coding exon 15 of the DSG2 gene, results from a C to G substitution at nucleotide position 3293. The serine at codon 1098 is replaced by cysteine, an amino acid with dissimilar properties. This alteration has been reported as a secondary cardiac variant in an exome cohort; however, clinical details are limited (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). This amino acid position is not well conserved in available vertebrate species, and cysteine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.