Submissions for variant NM_004415.4(DSP):c.2821C>T (p.Arg941Ter)

dbSNP: rs730880082

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181308	SCV000233601	pathogenic	not provided	2017-12-01	criteria provided, single submitter	clinical testing	p.Arg941Stop (CGA>TGA): c.2821 C>T in exon 20 of the DSP gene (NM_004415.2). The Arg941Stop nonsense mutation in the DSP gene has been reported previously in association with ARVC (Quarta G et al., 2011). This mutation is predicted to cause loss of normal protein function either due to production of an abnormal, prematurely truncated protein, or by absence of protein product due to nonsense mediated mRNA decay. Other nonsense mutations (Gln625Stop, Gln2667Stop) have been reported in the DSP gene associated with ARVC. Furthermore, Arg941Stop was not observed in 300 control individuals tested (Quarta G et al., 2011). Therefore, Arg941Stop in the DSP gene is interpreted as a disease-causing mutation. The variant is found in ARVC panel(s).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590295	SCV000698428	likely pathogenic	Familial isolated arrhythmogenic right ventricular dysplasia	2016-11-14	criteria provided, single submitter	clinical testing	Variant summary: The DSP c.2821C>T (p.Arg941X) variant results in a premature termination codon, predicted to cause a truncated or absent DSP protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. If NMD is escaped, the variant is expected to truncate spectrin/alpha-actinin domain and plectin repeats in the protein (InterPro). Truncations downstream of this position have been classified as likely pathogenic by our laboratory (e.g. p.Arg1738X, c.6273delA, etc.). This variant is absent in 121116 control chromosomes, including large and broad populations from ExAC. In literature, this variant has been reported in two ARVD patients/families (Quarta_2011, Gomes_2012). Multiple clinical laboratories have classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000698149	SCV000826792	pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-12-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg941*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with arrythmogenic right ventricular cardiomyopathy (PMID: 21606390). ClinVar contains an entry for this variant (Variation ID: 180326). For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001171092	SCV001333767	pathogenic	Cardiomyopathy	2018-07-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002433688	SCV002752218	pathogenic	Cardiovascular phenotype	2022-10-11	criteria provided, single submitter	clinical testing	The p.R941* pathogenic mutation (also known as c.2821C>T), located in coding exon 20 of the DSP gene, results from a C to T substitution at nucleotide position 2821. This changes the amino acid from an arginine to a stop codon within coding exon 20. This alteration has been reported in an individual with a clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC) (Quarta G et al. Circulation, 2011 Jun;123:2701-9; Gomes J et al. Eur Heart J, 2012 Aug;33:1942-53; Bariani R et al. Europace, 2021 06;23:907-917). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV002433688	SCV005882747	pathogenic	Cardiovascular phenotype	2025-01-10	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000157193	SCV000206917	likely pathogenic	Cardiac arrest	2014-09-04	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000181308	SCV001800560	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000181308	SCV001926488	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000181308	SCV001968284	pathogenic	not provided		no assertion criteria provided	clinical testing