ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.6496C>T (p.Arg2166Ter) (rs141026028)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181342 SCV000233639 pathogenic not provided 2016-08-16 criteria provided, single submitter clinical testing The R2166X variant in the DSP gene has been reported in at least one patient with ARVC (Bhonsale A et al., 2013). The R2166X variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Additionally, R2166X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Furthermore, other nonsense variants in the DSP gene have been reported in association with cardiomyopathy. In summary, R2166X in the DSP gene is interpreted as a disease-causing variant.
Ambry Genetics RCV000618020 SCV000736751 pathogenic Cardiovascular phenotype 2017-03-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Other strong data supporting pathogenic classification
Invitae RCV000641796 SCV000763446 likely pathogenic Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-12-26 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the DSP gene (p.Arg2166*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 706 amino acids of the DSP protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with arrhythmogenic right ventricular dysplasia/cardiomyopathy (PMID: 27532257, 23671136) and an individual affected with acantholytic epidermolysis bullosa (PMID: 28442525). ClinVar contains an entry for this variant (Variation ID: 199903). Other truncations (p.Lys2693Profs*3, p.Thr2733Serfs*14, p.Gln2765Alafs*23) that lie downstream of this variant have been reported in individuals affected with arrhythmogenic right ventricular cardiomyopathy or dilated cardiomyopathy (PMID: 28527814, 21859740). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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