Submissions for variant NM_001943.5(DSG2):c.2614G>C (p.Glu872Gln)

gnomAD frequency: 0.00001  dbSNP: rs754057911

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000621898	SCV000737775	uncertain significance	Cardiovascular phenotype	2016-11-03	criteria provided, single submitter	clinical testing	The p.E872Q variant (also known as c.2614G>C), located in coding exon 15 of the DSG2 gene, results from a G to C substitution at nucleotide position 2614. The glutamic acid at codon 872 is replaced by glutamine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 5954 samples (11908 alleles) with coverage at this position. Based on data from ExAC, the C allele has an overall frequency of less than 0.01% (1/119976). This amino acid position is well conserved in available 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000793087	SCV000932424	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2024-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 872 of the DSG2 protein (p.Glu872Gln). This variant is present in population databases (rs754057911, gnomAD 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: 519349). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt DSG2 protein function with a negative predictive value of 95%. 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.
Color Diagnostics, LLC DBA Color Health	RCV001191774	SCV001359674	uncertain significance	Cardiomyopathy	2023-12-04	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glutamine at codon 872 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 2/248450 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.
All of Us Research Program, National Institutes of Health	RCV004002679	SCV004821813	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2024-08-06	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glutamine at codon 872 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 2/248450 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.