Submissions for variant NM_004415.4(DSP):c.699G>A (p.Trp233Ter)

dbSNP: rs397516955

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038082	SCV000061748	pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2019-10-15	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000519036	SCV000617282	pathogenic	not provided	2022-12-16	criteria provided, single submitter	clinical testing	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; Published functional studies indicate this variant results in nonsense-mediated decay (Yang et al., 2006); Not observed in large population cohorts (gnomAD); Reported in ClinVar as pathogenic or likely pathogenic (ClinVar Variant ID# 44946; ClinVar); This variant is associated with the following publications: (PMID: 16917092, 27532257, 17363426, 20738328, 31402444, Atak2021[Computational], 34076677, 32372669, 34352074, 33684294, 28471438, 35325485, 36142674, 24503780)
Invitae	RCV000546646	SCV000639747	pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp233*) 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 individuals with autosomal dominant arrhythmogenic right ventricular cardiomyopathy (PMID: 16917092, 24503780; Invitae). ClinVar contains an entry for this variant (Variation ID: 44946). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763564	SCV000894395	pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8; Lethal acantholytic epidermolysis bullosa; Woolly hair-skin fragility syndrome; Keratosis palmoplantaris striata 2; Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis	2018-10-31	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852568	SCV000995269	likely pathogenic	Cardiomyopathy	2017-11-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001841580	SCV001338169	pathogenic	Cardiac arrhythmia	2020-02-21	criteria provided, single submitter	clinical testing	Variant summary: DSP c.699G>A (p.Trp233X) 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. In addition, in vitro studies of the affected patients blood cells support that this nonsense substitution results in haploinsufficiency, probably due to increased decay of nonsense mRNA (Yang_2006). Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251830 control chromosomes (gnomAD). c.699G>A has been reported in individuals affected with arrhythmogenic right ventricular cardiomyopathy (Yang_2006, ClinVar submitter) as well as one individual affected with dilated cardiomyopathy who was Caucasian adult and segregated with disease in at least on relative (Pugh_2014, ClinVar database SCV000061748.4). At least one in vitro study showed that this mutant results in DSP protein formed perinuclear aggregates and was neither localized at the cell membrane nor seen diffusively in the cytoplasm (Yang_2006). Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (3x) and likely pathogenic (2x). Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV002371833	SCV002668060	pathogenic	Cardiovascular phenotype	2022-07-13	criteria provided, single submitter	clinical testing	The p.W233* pathogenic mutation (also known as c.699G>A), located in coding exon 5 of the DSP gene, results from a G to A substitution at nucleotide position 699. This changes the amino acid from a tryptophan to a stop codon within coding exon 5. This alteration has been reported in dilated cardiomyopathy (DCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC) cohorts (Yang Z et al. Circ Res, 2006 Sep;99:646-55; Haggerty CM et al. Genet Med, 2017 11;19:1245-1252; Walsh R et al. Genet Med, 2017 02;19:192-203). 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.