ClinVar

Description

This variant is denoted Glu850Gln (aka E850Q) at the protein level and c.2548 G>C at the cDNA level. A heterozygous G>C nucleotide substitution was identified in exon 15 of the DSG2 gene, resulting in the replacement of an Glutamic acid codon (GAA) with a Glutamine codon (CAA) at amino acid position 850 in desmoglein-2. The Glu850Gln variant in the DSG2 gene has not been reported previously as a disease-causing mutation or as a benign polymorphism, to our knowledge. Glu850Gln results in a semi-conservative amino acid substitution of a negatively charged Glutamic acid with a neutral, polar Glutamine at a position that is not highly conserved. No mutations in nearby codons have been reported in association with ARVC, indicating this region of the protein may be tolerant of change. Additionally, in silico analysis predicts Glu850Gln is benign to the protein structure/function (Adzhubei IA et al., 2010; Schwarz JM et al., 2011). Nevertheless, Glu850Gln was not observed in approximately 4,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations (Exome Variant Server). Autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death in young individuals and athletes. It primarily affects the right ventricle; with time, it may also involve the left ventricle. The presentation of disease is highly variable even within families, and affected individuals may not always meet established clinical criteria. ARVC may be caused by mutations in at least seven genes, which together account for ARVC in 40-50% of patients (GeneReviews). At least 12% of patients with autosomal dominant arrhythmogenic right ventricular cardiomyopathy were reported to have a mutation in the DSG2 gene (GeneReviews; OMIM). The variant is found in ARVC panel(s).