ClinVar Miner

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

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Total submissions: 4
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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 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 pathogenic Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2019-10-30 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). This variant disrupts the C-terminus of the DSP protein. Other variant(s) that disrupt this region (p.Glu2728Glyfs*11) have been determined to be pathogenic (Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this allele has been classified as Pathogenic.
Color RCV001176348 SCV001340312 likely pathogenic Cardiomyopathy 2019-11-05 criteria provided, single submitter clinical testing

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