Submissions for variant NM_001943.5(DSG2):c.1605C>A (p.Asp535Glu)

dbSNP: rs368718022

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485939	SCV000570979	uncertain significance	not provided	2016-07-15	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the DSG2 gene. The D535E variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The D535E variant was not observed with any significant frequency in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. This substitution occurs at a position that is conserved across species. However, the D535E variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Finally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae	RCV000821976	SCV000962752	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2021-08-27	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid with glutamic acid at codon 535 of the DSG2 protein (p.Asp535Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is present in population databases (rs368718022, ExAC 0.002%). 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: 421691). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002402407	SCV002706418	uncertain significance	Cardiovascular phenotype	2022-06-14	criteria provided, single submitter	clinical testing	The p.D535E variant (also known as c.1605C>A), located in coding exon 11 of the DSG2 gene, results from a C to A substitution at nucleotide position 1605. The aspartic acid at codon 535 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is conserved. 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.
Fulgent Genetics, Fulgent Genetics	RCV002506171	SCV002816743	uncertain significance	Arrhythmogenic right ventricular dysplasia 10; Dilated cardiomyopathy 1BB	2021-09-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV003532142	SCV004363194	uncertain significance	Cardiomyopathy	2022-11-06	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glutamic acid at codon 535 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 not been reported in individuals affected with DSG2-related disorders in the literature. This variant has been identified in 1/249308 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.