ClinVar Genomic variation as it relates to human health
NM_004415.4(DSP):c.6478C>T (p.Arg2160Ter)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004415.4(DSP):c.6478C>T (p.Arg2160Ter)
Variation ID: 199902 Accession: VCV000199902.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6p24.3 6: 7583740 (GRCh38) [ NCBI UCSC ] 6: 7583973 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jul 16, 2020 Apr 20, 2024 Feb 5, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004415.4:c.6478C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004406.2:p.Arg2160Ter nonsense NM_001008844.3:c.4681C>T NP_001008844.1:p.Arg1561Ter nonsense NM_001319034.2:c.5149C>T NP_001305963.1:p.Arg1717Ter nonsense NC_000006.12:g.7583740C>T NC_000006.11:g.7583973C>T NG_008803.1:g.47104C>T LRG_423:g.47104C>T LRG_423t1:c.6478C>T - Protein change
- R2160*, R1561*, R1717*
- Other names
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- Canonical SPDI
- NC_000006.12:7583739:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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DSP | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
4694 | 4907 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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Aug 24, 2023 | RCV001206927.7 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 5, 2024 | RCV003996660.1 | |
Likely pathogenic (3) |
criteria provided, single submitter
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Nov 18, 2021 | RCV001529323.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 21, 2023 | RCV003454479.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Nov 18, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: yes
Allele origin:
germline
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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502798.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
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Likely pathogenic
(Sep 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular dysplasia 8
Affected status: unknown
Allele origin:
germline
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Clinical Genomics Laboratory, Washington University in St. Louis
Accession: SCV004177042.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
The DSP c.6478C>T (p.Arg2160Ter) variant has been reported in four individuals affected with arrhythmogenic right ventricular cardiomyopathy or dilated cardiomyopathy (Dal Ferro M et al., … (more)
The DSP c.6478C>T (p.Arg2160Ter) variant has been reported in four individuals affected with arrhythmogenic right ventricular cardiomyopathy or dilated cardiomyopathy (Dal Ferro M et al., PMID: 28416588; Gigli M et al., PMID: 31514951; ts Riele AS et al., PMID: 23810894; van Lint FHM et al., PMID: 31386562). One 25 year old individual was reported asymptomatic with a normal ECG but cardiac magnetic resonance showed mildly dilated left ventricle. The variant was inherited from an asymptomatic 59 year old father (Haggerty CM et al., PMID: 29997227). The variant is only observed on one allele out of 251,374 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors are uncertain as to the impact of this variant on DSP function. This variant causes a premature termination codon; however, because this occurs in the last exon, this is not predicted to lead to nonsense mediated decay. However, there are other predicted loss of function variants downstream that have been determined to be pathogenic that suggests this is a clinically significant region of the protein. This variant has been reported in the ClinVar database as a likely pathogenic variant in arrhythmogenic right ventricular cardiomyopathy or dilated cardiomyopathy by three submitters and pathogenic by one submitter. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic. (less)
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Pathogenic
(Aug 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic cardiomyopathy with wooly hair and keratoderma
Arrhythmogenic right ventricular dysplasia 8
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001378261.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 28, 2024 |
Comment:
This premature translational stop signal has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy or dilated cardiomyopathy (PMID: 23810894, 28416588). This sequence change creates … (more)
This premature translational stop signal has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy or dilated cardiomyopathy (PMID: 23810894, 28416588). This sequence change creates a premature translational stop signal (p.Arg2160*) in the DSP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 712 amino acid(s) of the DSP protein. This variant is present in population databases (rs777573018, gnomAD 0.002%). ClinVar contains an entry for this variant (Variation ID: 199902). 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. (less)
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Likely Pathogenic
(Feb 05, 2024)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic cardiomyopathy with wooly hair and keratoderma
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004834552.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This variant changes 1 nucleotide in exon 24 of the DSP gene, creating a premature translation stop signal in the last exon. This variant is … (more)
This variant changes 1 nucleotide in 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 alter the plakin repeat domain A where plankin repeat domains and downstream C-terminal sequence have been reported to be essential for interaction with intermediate filaments (PMID: 12101406, 12802069, 21756917). This variant has been reported in at least two unrelated individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 23810894, 25820315) and in an individual effected with dilated cardiomyopathy (PMID: 28416588). It has also been reported in an individual affected with premature atrial complexes (PMID: 29997227) and in an individual affected with Carvajal syndrome who also carried a second pathogenic truncation variant in the DSP gene (PMID: 37799505). This variant has been identified in 1/251374 chromosomes 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. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001742567.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001953370.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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A Novel Variant in the Desmoplakin Gene in One Case of the Rare Carvajal Syndrome with Dilated Cardiomyopathy: A Case Report and Literature Review. | Zhao XJ | Clinical, cosmetic and investigational dermatology | 2023 | PMID: 37799505 |
Genetic Risk of Arrhythmic Phenotypes in Patients With Dilated Cardiomyopathy. | Gigli M | Journal of the American College of Cardiology | 2019 | PMID: 31514951 |
Reevaluation of genetic variants previously associated with arrhythmogenic right ventricular cardiomyopathy integrating population-based cohorts and proteomics data. | Ye JZ | Clinical genetics | 2019 | PMID: 31402444 |
Arrhythmogenic Right Ventricular Cardiomyopathy-Associated Desmosomal Variants Are Rarely De Novo. | van Lint FHM | Circulation. Genomic and precision medicine | 2019 | PMID: 31386562 |
Managing Secondary Genomic Findings Associated With Arrhythmogenic Right Ventricular Cardiomyopathy: Case Studies and Proposal for Clinical Surveillance. | Haggerty CM | Circulation. Genomic and precision medicine | 2018 | PMID: 29997227 |
Association between mutation status and left ventricular reverse remodelling in dilated cardiomyopathy. | Dal Ferro M | Heart (British Cardiac Society) | 2017 | PMID: 28416588 |
Clinical Presentation, Long-Term Follow-Up, and Outcomes of 1001 Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Patients and Family Members. | Groeneweg JA | Circulation. Cardiovascular genetics | 2015 | PMID: 25820315 |
The implications of familial incidental findings from exome sequencing: the NIH Undiagnosed Diseases Program experience. | Lawrence L | Genetics in medicine : official journal of the American College of Medical Genetics | 2014 | PMID: 24784157 |
Incremental value of cardiac magnetic resonance imaging in arrhythmic risk stratification of arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated desmosomal mutation carriers. | te Riele AS | Journal of the American College of Cardiology | 2013 | PMID: 23810894 |
The nonlinear structure of the desmoplakin plakin domain and the effects of cardiomyopathy-linked mutations. | Al-Jassar C | Journal of molecular biology | 2011 | PMID: 21756917 |
Interaction of the bullous pemphigoid antigen 1 (BP230) and desmoplakin with intermediate filaments is mediated by distinct sequences within their COOH terminus. | Fontao L | Molecular biology of the cell | 2003 | PMID: 12802069 |
Structures of two intermediate filament-binding fragments of desmoplakin reveal a unique repeat motif structure. | Choi HJ | Nature structural biology | 2002 | PMID: 12101406 |
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Text-mined citations for rs777573018 ...
HelpRecord last updated May 01, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.