ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.3337C>T (p.Arg1113Ter) (rs746877365)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000475216 SCV000543269 pathogenic Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-06-22 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 1113 (p.Arg1113*) of the DSP gene. It is expected to result in an absent or disrupted protein product. Truncating variants in DSP are known to be pathogenic (PMID: 20716751). This particular truncation has been observed in several individuals with arrhythmogenic right ventricular cardiomyopathy (PMID:19095136, 19279339, 24070718) For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000521134 SCV000617283 pathogenic not provided 2019-01-07 criteria provided, single submitter clinical testing The R1113X variant in the DSP gene has been previously reported in multiple individuals with cardiomyopathy (Sen-Chowdhry et al., 2008; Asimaki et al., 2009; Zorzi et al., 2015). Sen-Chowdhry et al (2008) identified R1113X in a proband diagnosed with left-dominant arrhythmogenic cardiomyopathy and this variant segregated with disease in seven other affected family members. R1113X is predicted to cause loss of normal protein function either by protein truncation or 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 R1113X variant is not observed in large population cohorts (Lek et al., 2016). In summary, R1113X in the DSP gene is interpreted as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America 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 Clinical Services Laboratory,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.

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