ClinVar

Description

c.533dupT: p.His179AlafsX37 (H179AfsX37) in exon 3 of the PKP2 gene (NM_004572.3). The normal sequence with the base that is inserted in braces is: ACCC{T}GCAC. Although the c.533dupT mutation in the PKP2 gene has not been reported to our knowledge, this mutation causes a shift in reading frame starting at codon Histidine 179, changing it to an Alanine, and creating a premature stop codon at position 37 of the new reading frame, denoted p.His179AlafsX37. This mutation is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift mutations in the PKP2 gene have been reported in association with ARVC. The c.533dupT mutation in the PKP2 gene also has been observed in one other unrelated individuals at GeneDx. In summary, c.533dupT in the PKP2 gene is interpreted as a disease-causing mutation. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is primarily an autosomal dominant disease characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death (McNally E et al., 2009; Nava A et al., 2000). ARVC is most frequently caused by mutations in the genes encoding desmosomal proteins, complexes that maintain cell-to-cell connections and provide mechanical attachments among adjacent cells. Less commonly, ARVC may be caused by mutations in genes that encode proteins that maintain calcium homeostasis (McNally E et al., 2009). At least 11% of patients with autosomal dominant arrhythmogenic right ventricular cardiomyopathy were reported to have a mutation in the PKP2 gene (McNally E et al., 2009). The variant is found in ARVC panel(s).