Submissions for variant NM_004415.4(DSP):c.3337C>T (p.Arg1113Ter)

dbSNP: rs746877365

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000475216	SCV000543269	pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1113*) 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 arrhythmogenic right ventricular cardiomyopathy (PMID: 19095136, 19279339, 24070718). ClinVar contains an entry for this variant (Variation ID: 405247). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000521134	SCV000617283	pathogenic	not provided	2021-03-29	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID #405247; Landrum et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 19279339, 19095136, 21606390, 26138720, 24070718, 25820315, 25163546, 21606396, 25225338, 28527814, 30382575, 31386562, 31402444)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589386	SCV000698430	pathogenic	Long QT syndrome 1	2019-08-22	criteria provided, single submitter	clinical testing	Variant summary: DSP c.3337C>T (p.Arg1113X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 250498 control chromosomes (gnomAD and publication data). c.3337C>T has been reported in the literature heterozygous state in multiple individuals affected with Arrhythmia and ARVD/C (e.g. Cox_2011, Asimaki_2009, Sen-Chowdhry_2008, Haas_2015, Maruthappu_2019), including a large family where the variant co-segregated with the disease (Sen-Chowdhry_2008). In this family a (predominantly) left ventricular involvement was noted (Sen-Chowdhry_2008), and a curly hair phenotype was observed in all carriers, which was occasionally accompanied by a mild palmoplantar keratoderma (Maruthappu_2019). These data indicate that the variant is very likely to be associated with disease. Immunohistochemical and histology studies on cardiac tissue from carriers of the variant suggest a reduction in desmoplakin and an abnormal histology, respectively (Asimaki_2009, Sen-Chowdhry_2008). Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as pathogenic (2x) or likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic.
Illumina Laboratory Services, Illumina	RCV000778804	SCV000915184	likely pathogenic	DSP-Related Disorders	2018-08-29	criteria provided, single submitter	clinical testing	The DSP c.3337C>T (p.Arg1113Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. Sen-Chowdhry et al. (2009) reported a family segregating a cardiac phenotype of palpitations and presyncope, in which the proband suffered sudden cardiac death at age 35. The proband, her affected father and two affected sisters all carry the c.3337C>T (p.Arg1113Ter) variant, which is predicted to truncate approximately half of the DSP protein. The proband's two children also carry the variant, but at the time were asymptomatic. In addition, Asimaki et al. (2009) analyzed autopsy myocardium tissue from eleven cardiomyopathy ARVC subjects and ten unaffected controls for variants in the DSP gene, identifying the p.Arg1113Ter variant in one affected individual who suffered sudden cardiac death at age 36. The p.Arg1113Ter variant has not been reported in individuals with epidermolysis bullosa (lethal acantholytic), ectodermal dysplasia/skin fragility syndrome or skin fragility/woolly hair syndrome. Control data are not available for this variant which is not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium, or the Genome Aggregation Database. Based on the potential impact of stop-gained variants and supporting evidence from the literature, the p.Arg1113Ter variant is classified as likely pathogenic for DSP-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Color Diagnostics, LLC DBA Color Health	RCV001186299	SCV001352682	pathogenic	Cardiomyopathy	2021-06-29	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. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in several individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 19279339, 21606396, 21723241, 24070718) and with dilated cardiomyopathy (PMID: 25163546). It has been shown that this variant segregates with disease in two families affected with arrhythmogenic cardiomyopathy (PMID: 19095136, 30382575). This variant has not been identified 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.
Ambry Genetics	RCV002323682	SCV002605850	pathogenic	Cardiovascular phenotype	2023-02-01	criteria provided, single submitter	clinical testing	The p.R1113* pathogenic mutation (also known as c.3337C>T), located in coding exon 23 of the DSP gene, results from a C to T substitution at nucleotide position 3337. This changes the amino acid from an arginine to a stop codon within coding exon 23. This mutation was detected in a family with various cardiac phenotypes including palpitations and presyncope, in which the proband experienced sudden cardiac death at age 35 (Sen-Chowdhry S et al. J. Am. Coll. Cardiol., 2008 Dec;52:2175-87). In addition, this mutation was detected once in a sudden cardiac death cohort and authors used immunohistochemical and histology studies to show that this mutation diminished the level of desmoplakin compared to wild type (Asimaki A et al. N. Engl. J. Med., 2009 Mar;360:1075-84). This mutation has also been detected in several arrhythmia, dilated cardiomyopathy, and arrhythmogenic right ventricular dysplasia/cardiomyopathy cohorts (Cox MG et al. Circulation, 2011 Jun;123:2690-700; Groeneweg JA et al. Circ Cardiovasc Genet, 2015 Jun;8:437-46; Haas J et al. Eur. Heart J., 2015 May;36:1123-35a) including in a family who also presented with a curly hair and palmoplantar keratoderma phenotype (Maruthappu T et al. Br. J. Dermatol., 2019 May;180:1114-1122). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000521134	SCV001742548	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000521134	SCV001930814	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000521134	SCV001954147	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000521134	SCV001974501	pathogenic	not provided		no assertion criteria provided	clinical testing