ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.699G>A (p.Trp233Ter) (rs397516955)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000038082 SCV000061748 likely pathogenic Primary dilated cardiomyopathy; Arrhythmogenic right ventricular cardiomyopathy 2016-01-21 criteria provided, single submitter clinical testing The p.Trp233X variant in DSP has been reported in 1 individual with ARVC (Yang 2 006). It has been identified by our laboratory in 1 Caucasian adult with DCM and segregated with disease in 1 affected relative (Pugh 2014, LMM unpublished data ). It was absent from large population studies (dbSNP rs397516955). This nonsens e variant leads to a premature termination codon at position 233, which is predi cted to lead to a truncated or absent protein. In vitro studies of blood cells o f the reported individual demonstrated likely loss of the variant allele, presum ably through nonsense mediated decay (Yang 2006). Nonsense and other truncating variants in DSP are strongly associated with ARVC, and there is evidence to supp ort that it may play a role in the genetic etiology of DCM. In summary, although additional studies are required to fully establish its clinical significance, t he p.Trp233X variant is likely pathogenic.
GeneDx RCV000519036 SCV000617282 pathogenic not provided 2018-05-16 criteria provided, single submitter clinical testing The W233X variant has been reported in one individual from the North American ARVD/C Registry and one individual with DCM (Yang et al., 2006; Pugh et al., 2014; Walsh et al., 2017). The variant is reported as likely pathogenic in ClinVar by the same clinical laboratry who published the proband with DCM, and, in ClinVar, they report this variant segregated with disease in at least on relative (ClinVar SCV000061748.4; Landrum et al., 2016). Introduction of W233X in vitro resulted in DSP-protein aggregates that neither localized to the cell membrane nor were present in the cytoplasm (Yang et al., 2006). This was concordant with the the absence of the W233X variant in patient cDNA amplified from the lymphoblastoid cell, and supports haploinsufficiency through nonsense-mediated mRNA decay. Other nonsense variants in the DSP gene have been reported in Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014). Furthermore, the W233X variant is not observed in large population cohorts (Lek et al., 2016).
Invitae RCV000546646 SCV000639747 pathogenic Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-09-13 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. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 16917092, Invitae) and dilated cardiomyopathy (PMID: 24503780). ClinVar contains an entry for this variant (Variation ID: 44946). Loss-of-function variants in DSP are known to be pathogenic (PMID: 24503780, 20716751). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000763564 SCV000894395 pathogenic Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8; Epidermolysis bullosa, lethal acantholytic; Skin fragility woolly hair syndrome; Keratosis palmoplantaris striata II; Cardiomyopathy, dilated, with woolly 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

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