Submissions for variant NM_004415.4(DSP):c.6393del (p.Gly2133fs)

dbSNP: rs730880093

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000788472	SCV003805991	likely pathogenic	not provided	2022-08-02	criteria provided, single submitter	clinical testing	Reported in individuals with DCM (Gigli et al., 2019; Verdonschot et al., 2020); Frameshift 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: 31514951, 32880476)
Labcorp Genetics (formerly Invitae), Labcorp	RCV003764989	SCV004579541	pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2023-07-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly2133Valfs*2) in the DSP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 739 amino acid(s) of the DSP protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with autosomal dominant DSP-related conditions (PMID: 31514951, 32880476, 34352074). ClinVar contains an entry for this variant (Variation ID: 180344). 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	RCV003998335	SCV004842753	likely pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2023-12-18	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 24 of the DSP gene, creating a frameshift and premature translation stop signal in the last exon. Although functional studies have not been reported, this variant is expected to alters the C-terminal plakin repeat domain A (a.a. 1960-2208), plakin repeat domain B (a.a. 2244-2446) and plakin repeat domain C (a.a. 2609-2822), which 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: 246676, 263803, 518482). This variant has been reported in at least three unrelated individuals affected with dilated cardiomyopathy (PMID: 31514951, 32880476, 34194005; ClinVar: SCV000206941.2). 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.
Blueprint Genetics	RCV000157217	SCV000206941	likely pathogenic	Primary dilated cardiomyopathy	2014-09-29	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000788472	SCV001919521	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000788472	SCV001954832	likely pathogenic	not provided		no assertion criteria provided	clinical testing