ClinVar Genomic variation as it relates to human health
NM_004415.4(DSP):c.7217C>G (p.Ser2406Ter)
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.7217C>G (p.Ser2406Ter)
Variation ID: 1326970 Accession: VCV001326970.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6p24.3 6: 7584479 (GRCh38) [ NCBI UCSC ] 6: 7584712 (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 Dec 12, 2021 Apr 20, 2024 Nov 9, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004415.4:c.7217C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004406.2:p.Ser2406Ter nonsense NM_001008844.3:c.5420C>G NP_001008844.1:p.Ser1807Ter nonsense NM_001319034.2:c.5888C>G NP_001305963.1:p.Ser1963Ter nonsense NC_000006.12:g.7584479C>G NC_000006.11:g.7584712C>G NG_008803.1:g.47843C>G LRG_423:g.47843C>G LRG_423t1:c.7217C>G - Protein change
- S1807*, S1963*, S2406*
- Other names
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- Canonical SPDI
- NC_000006.12:7584478:C:G
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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.
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- 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
Help
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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Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 15, 2023 | RCV001788848.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 9, 2023 | RCV001885208.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 20, 2023 | RCV003533029.1 |
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
(Jun 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV004363497.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
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 with disrupted plakin repeat domain B (a.a. 2244-2446) 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 an individual suspected of having arrhythmogenic right ventricular cardiomyopathy (ClinVar SCV002029239.2). 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. (less)
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Pathogenic
(Nov 09, 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: SCV002234251.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Ser2406*) in the DSP gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Ser2406*) in the DSP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 466 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 arrhythmogenic right ventricular cardiomyopathy (PMID: 25825460). ClinVar contains an entry for this variant (Variation ID: 1326970). 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
(Mar 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic cardiomyopathy with wooly hair and keratoderma
Affected status: yes
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002029239.3
First in ClinVar: Dec 12, 2021 Last updated: Apr 15, 2024 |
Comment:
This sequence change in DSP is a nonsense variant that may cause a premature stop codon (p.(Ser2406*)) that is predicted to escape nonsense mediated decay, … (more)
This sequence change in DSP is a nonsense variant that may cause a premature stop codon (p.(Ser2406*)) that is predicted to escape nonsense mediated decay, however it is a truncation of a functionally important region (removes 466 amino acids) in a gene where loss-of-function is an established disease mechanism (PMID: 28527814, 32005173). This variant is absent from gnomAD v2.1 and v3.1. To our knowledge, this variant has not been reported in the literature in any individuals with DSP-related disease. At least one patient with this variant displayed a phentoype highly consistent with DSP-related arrhythmogenic right ventricular cardiomyopathy (Royal Melbourne Hospital). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PVS1_Strong, PM2_Supporting, PP4. (less)
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Likely Pathogenic
(Aug 15, 2023)
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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: SCV004817160.1
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 with disrupted plakin repeat domain B (a.a. 2244-2446) 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 an individual suspected of having DSP-related arrhythmogenic right ventricular cardiomyopathy (ClinVar SCV002029239.2). 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. (less)
Number of individuals with the variant: 2
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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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DSP p.(Thr2104Glnfs*12) variant presents variably with early onset severe arrhythmias and left ventricular cardiomyopathy. | Heliö K | BMC medical genetics | 2020 | PMID: 32005173 |
Desmoplakin missense and non-missense mutations in arrhythmogenic right ventricular cardiomyopathy: Genotype-phenotype correlation. | Castelletti S | International journal of cardiology | 2017 | PMID: 28527814 |
Arrhythmic risk assessment in genotyped families with arrhythmogenic right ventricular cardiomyopathy. | Protonotarios A | Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology | 2016 | PMID: 25825460 |
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 |
Text-mined citations for rs2113701867 ...
HelpRecord last updated Jun 02, 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.