ClinVar Genomic variation as it relates to human health

This variant, formerly titled ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 11, has been reclassified based on the findings of De Bortoli et al. (2010). In affected members of 3 unrelated families with ARVD11 (610476), Syrris et al. (2006) identified a heterozygous 2-bp insertion (2687insGA) in exon 17 of the DSC2 gene, resulting in a frameshift and premature termination (Glu896fsTer900; E896fsX900). Haplotype analysis suggested that this was a recurrent mutation rather than a founder mutation. The mutation was not found in 200 ethnically matched controls. De Bortoli et al. (2010) detected the Glu896fsTer900 variation, which they designated Ala897LysfsTer4 (A897KfsX4), in 5 unrelated Italian ARVD probands, 4 of whom carried mutations in other known ARVD genes as well. The A897KfsX4 variant was also found in 6 of 400 control chromosomes (allele frequency, 1.5%). The authors noted that the A897KfsX4 variation affects the last 5 amino acids of the DSC2a isoform and not those of the DSC2b, which shows higher expression in heart than does DSC2a, suggesting that relative deficiency of DSC2a might be compensated for by DSC2b. Transfection studies using the desmosome-forming atrial cardiomyocyte cell line HL-1 showed that the A897KfsX4 mutant DSC2 localized in the cytoplasm whereas wildtype localized in the plasma membrane; however, immunostaining showed the presence of well-assembled desmosomes, with no colocalization between endogenous dsg and mutant DSC2. De Bortoli et al. (2010) suggested that A897KfsX4 should be considered a rare polymorphism. (less)