ClinVar Genomic variation as it relates to human health
NM_004415.4(DSP):c.88G>A (p.Val30Met)
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.
Uncertain significance(3); Benign(3); Likely benign(12)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004415.4(DSP):c.88G>A (p.Val30Met)
Variation ID: 16846 Accession: VCV000016846.58
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6p24.3 6: 7542003 (GRCh38) [ NCBI UCSC ] 6: 7542236 (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 6, 2014 May 12, 2024 Apr 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004415.4:c.88G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004406.2:p.Val30Met missense NM_001008844.3:c.88G>A NP_001008844.1:p.Val30Met missense NM_001319034.2:c.88G>A NP_001305963.1:p.Val30Met missense NC_000006.12:g.7542003G>A NC_000006.11:g.7542236G>A NG_008803.1:g.5367G>A LRG_423:g.5367G>A LRG_423t1:c.88G>A - Protein change
- V30M
- Other names
- p.V30M:GTG>ATG
- DSP, VAL30MET (rs121912998)
- Canonical SPDI
- NC_000006.12:7542002:G:A
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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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0.00220 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00159
1000 Genomes Project 30x 0.00219
1000 Genomes Project 0.00220
The Genome Aggregation Database (gnomAD) 0.00094
Trans-Omics for Precision Medicine (TOPMed) 0.00123
Exome Aggregation Consortium (ExAC) 0.00311
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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 | |
DSP-AS1 | - | - | - | GRCh38 | - | 188 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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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Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Jan 1, 2019 | RCV000018340.37 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jun 25, 2015 | RCV000029685.11 | |
Benign/Likely benign (6) |
criteria provided, multiple submitters, no conflicts
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Oct 11, 2021 | RCV000038118.17 | |
Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Jul 27, 2018 | RCV000234980.5 | |
no classifications from unflagged records (1) |
no classifications from unflagged records
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Oct 12, 2023 | RCV000415109.3 | |
Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
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Apr 1, 2024 | RCV000724208.29 | |
Benign (1) |
criteria provided, single submitter
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Oct 30, 2018 | RCV000619218.3 | |
Likely benign (1) |
criteria provided, single submitter
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Mar 6, 2018 | RCV001164369.4 | |
no classifications from unflagged records (1) |
no classifications from unflagged records
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Oct 12, 2023 | RCV001198383.3 | |
Benign (1) |
criteria provided, single submitter
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Jan 31, 2024 | RCV001083215.5 | |
Likely benign (1) |
criteria provided, single submitter
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Mar 6, 2018 | RCV001164370.4 | |
DSP-related disorder
|
Likely benign (1) |
criteria provided, single submitter
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Sep 12, 2022 | RCV003904847.1 |
Likely benign (1) |
criteria provided, single submitter
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Feb 5, 2024 | RCV003996108.2 | |
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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
Help
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
Help
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
Help
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 benign
(Mar 14, 2018)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000910778.1
First in ClinVar: May 20, 2019 Last updated: May 20, 2019 |
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Benign
(Jan 31, 2024)
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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: SCV000288553.10
First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024 |
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Likely benign
(Sep 12, 2022)
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criteria provided, single submitter
Method: clinical testing
|
DSP-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004723388.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Likely benign
(Apr 01, 2024)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001745920.15
First in ClinVar: Jul 10, 2021 Last updated: May 12, 2024 |
Comment:
DSP: BS2
Number of individuals with the variant: 22
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Likely benign
(Jun 24, 2013)
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criteria provided, single submitter
Method: research
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Cardiomyopathy, arrhythmogenic right ventricular
Affected status: unknown
Allele origin:
unknown
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Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000051381.2 First in ClinVar: Jun 08, 2015 Last updated: Sep 14, 2015
Comments (2):
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for … (more)
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for details. (less)
Medical sequencing
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Number of individuals with the variant: 1
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Uncertain significance
(Jun 25, 2015)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular cardiomyopathy
Affected status: unknown
Allele origin:
unknown
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Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000257974.2
First in ClinVar: Sep 14, 2015 Last updated: Sep 14, 2015 |
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Uncertain significance
(Mar 24, 2015)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000224441.5
First in ClinVar: Jun 29, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 4
Sex: mixed
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Uncertain significance
(Nov 21, 2018)
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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:
unknown
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV000883082.1
First in ClinVar: Apr 13, 2016 Last updated: Apr 13, 2016 |
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Likely benign
(Apr 03, 2015)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000061784.5
First in ClinVar: May 03, 2013 Last updated: Apr 09, 2018 |
Comment:
p.Val30Met in exon 1 of DSP: This variant is not expected to have clinical signi ficance due to a lack of conservation across species, including … (more)
p.Val30Met in exon 1 of DSP: This variant is not expected to have clinical signi ficance due to a lack of conservation across species, including mammals. Of note , multiple mammals, including several primates, have a methionine (Met) at this position. This strongly argues against a disease causing role, though a modifyin g effect cannot be excluded. In addition, it has been identified in 0.6% (57/99 98) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http:/ /exac.broadinstitute.org; dbSNP rs12192998). Of note, this variant has been publ ished by several studies (http://arvcdatabase.info/), though the data provided b y these studies is uninformative. (less)
Number of individuals with the variant: 8
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Likely benign
(Mar 06, 2018)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic cardiomyopathy with wooly hair and keratoderma
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001326492.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
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Likely benign
(Mar 06, 2018)
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criteria provided, single submitter
Method: clinical testing
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Lethal acantholytic epidermolysis bullosa
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001326493.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
|
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Likely benign
(Mar 06, 2018)
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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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Illumina Laboratory Services, Illumina
Accession: SCV000464829.3
First in ClinVar: Sep 14, 2015 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
|
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Likely benign
(Jul 27, 2018)
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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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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV001333544.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
|
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Likely benign
(Jan 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular dysplasia 8
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440500.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
|
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Likely benign
(Aug 20, 2020)
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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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GeneDx
Accession: SCV000233655.11
First in ClinVar: May 27, 2015 Last updated: Apr 09, 2018 |
Comment:
This variant is associated with the following publications: (PMID: 32268277, 31028938, 25637381, 16917092, 20152563, 21636032, 23137101, 23671136, 24070718, 20129281, 23861362, 26656175, 27153395, 26332594, 26569459, 23299917, … (more)
This variant is associated with the following publications: (PMID: 32268277, 31028938, 25637381, 16917092, 20152563, 21636032, 23137101, 23671136, 24070718, 20129281, 23861362, 26656175, 27153395, 26332594, 26569459, 23299917, 28473349, 25985138, 27435932, 28798025, 31019283, 31402444, 33232181) (less)
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Benign
(Oct 11, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000052337.3
First in ClinVar: Apr 04, 2013 Last updated: Nov 20, 2021 |
Comment:
Variant summary: DSP c.88G>A (p.Val30Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more)
Variant summary: DSP c.88G>A (p.Val30Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 212604 control chromosomes, predominantly at a frequency of 0.0043 within the South Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 22 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.0002), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.88G>A has been reported in the literature in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (e.g. Yang_2006, Bauce_2010, Xu_2010, Rasmussen_2013, Rasmussen_2013, Bhonsale_2013, Rigato_2013). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Rasmussen_2012). Fourteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Benign/likely benign n=9, VUS n=3). Based on the evidence outlined above, the variant was classified as benign. (less)
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Likely Benign
(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
|
All of Us Research Program, National Institutes of Health
Accession: SCV004822021.1
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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Number of individuals with the variant: 359
|
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Benign
(Oct 30, 2018)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000735953.5
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more)
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001741376.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
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Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001922801.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
|
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Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001931049.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
|
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Uncertain significance
(Sep 15, 2006)
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no assertion criteria provided
Method: literature only
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RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000038619.4
First in ClinVar: Apr 04, 2013 Last updated: Jun 17, 2023 |
Comment on evidence:
This variant, formerly titled ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 8, has been reclassified because its contribution to the phenotype has not been confirmed. In a … (more)
This variant, formerly titled ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 8, has been reclassified because its contribution to the phenotype has not been confirmed. In a patient with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD8; 607450), Yang et al. (2006) identified an c.88G-A transition in the DSP gene, resulting in a val30-to-met (V30M) substitution. Hamosh (2016) noted that the c.88G-A mutation (rs121912998) was identified in 149 of 47,946 alleles in the ExAC browser (January 6, 2016). One individual was homozygous for the variant. (less)
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Likely benign
(Jun 01, 2014)
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no assertion criteria provided
Method: research
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Cardiomyopathy, arrhythmogenic right ventricular
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190177.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014
Comment:
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
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Pathogenic
(Mar 27, 2015)
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no assertion criteria provided
Method: clinical testing
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Cardiomyopathy
Affected status: yes
Allele origin:
unknown
|
Forensic Genetics Laboratory, Harris County Institute of Forensic Sciences
Study: HCIFS-Postmortem genetic screening project
Accession: SCV000263110.1 First in ClinVar: Jul 15, 2016 Last updated: Jul 15, 2016 |
Clinical Features:
Cardiomyopathy (present) , Sudden death (present)
Age: 10-19 years
Sex: male
Ethnicity/Population group: Causasians
Tissue: Blood
|
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Uncertain significance
(Feb 06, 2014)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: not provided
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280098.1
First in ClinVar: May 27, 2015 Last updated: May 27, 2015 |
Comment:
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case … (more)
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Based on the data reviewed below, we consider this a variant of uncertain significance. This variant has been identified in multiple probands with ARVC and in one SCICD center patient with conduction system disease, biventricular dysfunction and a history of SCD. Yang et al (2006) first reported the variant in an individual with ARVC in a publication that only reports on DSP variants. In all other published cases this variant occurs with additional variants. Bauce et al (2010) identified an individual with ARVC and two DSP variants, p.Val30Met and p.Arg2541Lys. Each variant was detected in isolation in separate affected family members. Xu et al (2010) report a proband with the p.Val30Met variant as well as a nonsense and a missense variant in the PKP2 gene. This is a conservative amino acid change with the replacement on a nonpolar Valine with a nonpolar Methionine. Valine is not conserved across species and several species harbor a Methionine at this codon. In vitro studies reported by Yang et al (2006) showed that when this variant is present desmoplakin is trapped in the cytoplasm and fails to localize to the cell membrane. In total the variant has been seen in 21 of 9109 published controls and publicly available general population samples (as of 12/6/14). Across available publications the variant is absent in 1150 presumably healthy control individuals. However, more recently Kapplinger et al (2011) reported the variant in 1 of 427 presumably healthy individuals and the variant is reported in 16 of 4,269 European individuals in the NHLBI Exome Sequencing Project dataset and 0 of 2169 African American individuals (as of 2/6/14). It is also reported in dbSNP (rs 121912998), though this seems to point to the NHLBI data. It was also seen in 4 of 1094 individuals in the 1000 genomes low coverage data. (less)
Number of individuals with the variant: 4
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001798290.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
|
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Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
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: SCV001957805.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
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Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001973708.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Likely pathogenic
(Dec 13, 2013)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Right ventricular cardiomyopathy
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000492954.1
First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017 |
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Likely pathogenic
(Jan 01, 2016)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Keratosis palmoplantaris striata 2
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001369295.2
First in ClinVar: Jul 06, 2020 Last updated: Jul 06, 2020 |
Comment:
This variant was classified as: Likely pathogenic.
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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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Use of Clinical Exome Sequencing in Isolated Congenital Heart Disease. | Zahavich L | Circulation. Cardiovascular genetics | 2017 | PMID: 28473349 |
Postmortem genetic screening for the identification, verification, and reporting of genetic variants contributing to the sudden death of the young. | Methner DN | Genome research | 2016 | PMID: 27435932 |
Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer. | Maxwell KN | American journal of human genetics | 2016 | PMID: 27153395 |
Molecular analysis of sarcomeric and non-sarcomeric genes in patients with hypertrophic cardiomyopathy. | Bottillo I | Gene | 2016 | PMID: 26656175 |
Myocardial expression profiles of candidate molecules in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia compared to those with dilated cardiomyopathy and healthy controls. | Akdis D | Heart rhythm | 2016 | PMID: 26569459 |
iASPP, a previously unidentified regulator of desmosomes, prevents arrhythmogenic right ventricular cardiomyopathy (ARVC)-induced sudden death. | Notari M | Proceedings of the National Academy of Sciences of the United States of America | 2015 | PMID: 25691752 |
Compound and digenic heterozygosity predicts lifetime arrhythmic outcome and sudden cardiac death in desmosomal gene-related arrhythmogenic right ventricular cardiomyopathy. | Rigato I | Circulation. Cardiovascular genetics | 2013 | PMID: 24070718 |
A systematic approach to assessing the clinical significance of genetic variants. | Duzkale H | Clinical genetics | 2013 | PMID: 24033266 |
Interpreting secondary cardiac disease variants in an exome cohort. | Ng D | Circulation. Cardiovascular genetics | 2013 | PMID: 23861362 |
Risk stratification in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated desmosomal mutation carriers. | Bhonsale A | Circulation. Arrhythmia and electrophysiology | 2013 | PMID: 23671136 |
Mutated desmoglein-2 proteins are incorporated into desmosomes and exhibit dominant-negative effects in arrhythmogenic right ventricular cardiomyopathy. | Rasmussen TB | Human mutation | 2013 | PMID: 23381804 |
New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants. | Andreasen C | European journal of human genetics : EJHG | 2013 | PMID: 23299917 |
Protein expression studies of desmoplakin mutations in cardiomyopathy patients reveal different molecular disease mechanisms. | Rasmussen TB | Clinical genetics | 2013 | PMID: 23137101 |
Distinguishing arrhythmogenic right ventricular cardiomyopathy/dysplasia-associated mutations from background genetic noise. | Kapplinger JD | Journal of the American College of Cardiology | 2011 | PMID: 21636032 |
Compound and digenic heterozygosity contributes to arrhythmogenic right ventricular cardiomyopathy. | Xu T | Journal of the American College of Cardiology | 2010 | PMID: 20152563 |
Multiple mutations in desmosomal proteins encoding genes in arrhythmogenic right ventricular cardiomyopathy/dysplasia. | Bauce B | Heart rhythm | 2010 | PMID: 20129281 |
Desmosomal dysfunction due to mutations in desmoplakin causes arrhythmogenic right ventricular dysplasia/cardiomyopathy. | Yang Z | Circulation research | 2006 | PMID: 16917092 |
Hamosh, A. Personal Communication. 2016. Baltimore, Md. | - | - | - | - |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=DSP | - | - | - | - |
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Text-mined citations for rs121912998 ...
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.