Submissions for variant NM_004415.4(DSP):c.7000C>T (p.Arg2334Ter)

gnomAD frequency: 0.00001  dbSNP: rs369482721

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001191443	SCV001359264	uncertain significance	Cardiomyopathy	2019-06-01	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in the last exon 24 of the DSP gene, creating a premature translation stop signal. This variant is expected to result in an absent or truncated protein product lacking the last 538 amino acids. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002560978	SCV003221058	pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg2334*) in the DSP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 538 amino acid(s) of the DSP protein. This variant is present in population databases (rs369482721, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with DSP-related conditions. ClinVar contains an entry for this variant (Variation ID: 927872). 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. For these reasons, this variant has been classified as Pathogenic.
All of Us Research Program, National Institutes of Health	RCV004807450	SCV005429033	likely pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2024-07-29	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in the exon 24 of the DSP gene, creating a premature translation stop signal in the last exon. This variant is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. Although functional studies have not been reported, this variant is expected to disrupt the plakin repeat domain B and C. Plakin repeat domains and downstream C-terminal sequence have been reported to be essential for interaction with intermediate filaments (PMID: 12101406, 12802069, 21756917). In addition, truncating variants occurring downstream of this variant are known to be disease-causing (ClinVar variation ID: 923199, 263803). This variant has been reported in an individual affected with arrhythmogenic cardiomyopathy. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of DSP function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.