Submissions for variant NM_004415.4(DSP):c.4372C>T (p.Arg1458Ter)

dbSNP: rs28763965

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000641778	SCV000763427	pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-10-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1458*) in the DSP gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DSP are known to be pathogenic (PMID: 20716751, 24503780, 25227139). This variant is present in population databases (rs28763965, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with clinical features of DSP-related conditions (PMID: 28359509, 32410525). ClinVar contains an entry for this variant (Variation ID: 534283). For these reasons, this variant has been classified as Pathogenic.
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852574	SCV000995275	likely pathogenic	Cardiomyopathy	2017-03-17	criteria provided, single submitter	clinical testing
Klaassen Lab, Charite University Medicine Berlin	RCV002060746	SCV002495741	likely pathogenic	Myocarditis		criteria provided, single submitter	research
Ambry Genetics	RCV002331174	SCV002632984	pathogenic	Cardiovascular phenotype	2021-07-22	criteria provided, single submitter	clinical testing	The p.R1458* pathogenic mutation (also known as c.4372C>T), located in coding exon 23 of the DSP gene, results from a C to T substitution at nucleotide position 4372. This changes the amino acid from an arginine to a stop codon within coding exon 23. This mutation has been reported in individuals with dilated cardiomyopathy (DCM) and in cardiomyopathy cohorts with limited details (Janin A et al. Clin Genet, 2017 Dec;92:616-623; Smith ED et al. Circulation, 2020 Jun;141:1872-1884). This alteration was also detected in a homozygous child with acute myocarditis and DCM-related findings; his heterozygous parents were reportedly unaffected (Belkaya S et al. J Am Coll Cardiol, 2017 Apr;69:1653-1665). In addition, this variant was described in a family with two heterozygous brothers affected with acute myocarditis and woolly hair, one of whom had non-sustained ventricular tachycardia; their heterozygous mother was unaffected (Poller W et al. J Am Heart Assoc, 2020 05;9:e015289). 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 alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
All of Us Research Program, National Institutes of Health	RCV004003925	SCV004834548	pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2024-01-22	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 23 of the DSP gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in heterozygous state in a few young individuals affected with myocarditis as well as in an unaffected family member (PMID: 32410525, 34213952). This variant has also been reported in homozygous state in a young individual affected with acute myocarditis and severely dilated left ventricle (PMID: 28359509). This variant has been identified in 1/251254 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of DSP function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.