ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.5851C>T (p.Arg1951Ter)

dbSNP: rs869025395
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000208287 SCV000263878 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy 2015-06-08 criteria provided, single submitter clinical testing
GeneDx RCV000427986 SCV000534595 pathogenic not provided 2022-06-17 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26656175, 32372669, 26899768, 31402444, Reza_2022_Cardiogenetics)
Invitae RCV000529617 SCV000639746 pathogenic Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8 2023-05-25 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the DSP protein in which other variant(s) (p.Glu2728Glyfs*11) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 222582). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 26899768). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg1951*) in the DSP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 921 amino acid(s) of the DSP protein.
Color Diagnostics, LLC DBA Color Health RCV001187850 SCV001354743 pathogenic Cardiomyopathy 2023-06-22 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 24 of the DSP gene, creating a premature translation stop signal in the last exon. Although functional studies have not been reported, this variant is predicted to escape nonsense-mediated decay and be expressed as a truncated protein with disruption to the plakin repeat domains and downstream C-terminal sequence that have been reported to be essential for interaction with intermediate filaments (PMID: 12101406, 12802069, 21756917). This variant has been reported in 6 unrelated individuals affected with arrhythmogenic cardiomyopathy (PMID: 35474678, 36768812, Delpon 2016, Burns 2019, dissertation, The University of Sydney), in 1 individual affected with familial dilated cardiomyopathy (PMID: 26899768), hypertrophic cardiomyopathy (PMID: 26656175), and acute myocarditis (PMID: 34368507). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Sangiuolo Lab - Medical Genetics Laboratory, Tor Vergata University RCV002515542 SCV003760914 pathogenic Arrhythmogenic cardiomyopathy 2023-01-10 no assertion criteria provided clinical testing

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