ClinVar

Description

The p.R1267* pathogenic mutation (also known as c.3799C>T), located in coding exon 23 of the DSP gene, results from a C to T substitution at nucleotide position 3799. This changes the amino acid from an arginine to a stop codon within coding exon 23. Alterations in DSP that result in haploinsufficiency or protein truncation have been reported in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) and dilated cardiomyopathy (DCM) (Fressart V et al. Europace. 2010;12(6):861-8; Elliott P et al. Circ Cardiovasc Genet. 2010;3(4):314-22; Quarta G et al. Circulation. 2011;123(23):2701-9; Garcia-Pavia P et al. Heart. 2011;97(21):1744-52; Rasmussen TB et al. Clin Genet. 2013;84(1):20-30; Pugh TJ et al. Genet Med. 2014;16(8):601-8). This particular variant has been reported in the homozygous state in a subject with left and right ventricular involvement, wooly hair and palmar keratoderma (Uzumcu A et al. J. Med. Genet., 2006 Feb;43:e5). This variant has also been reported in the compound heterozygous state in two siblings with dilated cardiomyopathy (DCM) (Surmacz R et al. Pol. Arch. Intern. Med., 2018 12;128:785-787). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.