ClinVar Genomic variation as it relates to human health
NM_001943.5(DSG2):c.874C>T (p.Arg292Cys)
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_001943.5(DSG2):c.874C>T (p.Arg292Cys)
Variation ID: 466351 Accession: VCV000466351.37
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q12.1 18: 31524748 (GRCh38) [ NCBI UCSC ] 18: 29104711 (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 Oct 10, 2018 Apr 20, 2024 Jan 13, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001943.5:c.874C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001934.2:p.Arg292Cys missense NC_000018.10:g.31524748C>T NC_000018.9:g.29104711C>T NG_007072.3:g.31507C>T LRG_397:g.31507C>T LRG_397t1:c.874C>T - Protein change
- R292C
- Other names
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- Canonical SPDI
- NC_000018.10:31524747: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 0.00005
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
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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DSG2 | Some evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1092 | 1881 |
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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Uncertain significance (2) |
criteria provided, single submitter
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Jan 13, 2024 | RCV000545942.12 | |
Uncertain significance (5) |
criteria provided, multiple submitters, no conflicts
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Dec 13, 2022 | RCV000996666.15 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jan 5, 2024 | RCV000845455.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 20, 2023 | RCV001180821.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 7, 2020 | RCV002377091.1 |
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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Uncertain significance
(-)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular cardiomyopathy
Affected status: yes
Allele origin:
germline
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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000987544.1
First in ClinVar: Sep 08, 2019 Last updated: Sep 08, 2019 |
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Uncertain significance
(Apr 02, 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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GeneDx
Accession: SCV001789066.1
First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30454721, … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30454721, 21606396, 28097316, 25820315, 22000064, 22214898, 27532257, 29178656) (less)
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Uncertain significance
(Dec 07, 2020)
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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: SCV002685079.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.R292C variant (also known as c.874C>T), located in coding exon 8 of the DSG2 gene, results from a C to T substitution at nucleotide … (more)
The p.R292C variant (also known as c.874C>T), located in coding exon 8 of the DSG2 gene, results from a C to T substitution at nucleotide position 874. The arginine at codon 292 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple arrhythmogenic right ventricular cardiomyopathy (ARVC) cohorts (Groeneweg JA et al. Circ Cardiovasc Genet, 2015 Jun;8:437-46; Te Riele ASJM et al. JACC Clin Electrophysiol, 2015 Dec;1:551-560; Walsh R et al. Genet. Med., 2017 02;19:192-203). However, in many probands this alteration was detected in the homozygous or compound heterozygous state or co-occurred with alterations in other ARVC-associated genes, and a number of relatives positive for the R292C alteration were reported to be unaffected (Cox MG et al. Circulation, 2011 Jun;123:2690-700; Sato T et al. Leg Med (Tokyo), 2011 Nov;13:298-300; Nakajima T et al. Circ. J., 2012 Dec;76:737-43; Wada Y et al. Mol Genet Genomic Med, 2017 11;5:639-651). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Dec 13, 2022)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001712935.2
First in ClinVar: Jun 15, 2021 Last updated: Jan 26, 2024 |
Number of individuals with the variant: 2
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Uncertain significance
(Jan 13, 2024)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular dysplasia 10
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000641996.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 292 of the DSG2 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 292 of the DSG2 protein (p.Arg292Cys). This variant is present in population databases (rs770921270, gnomAD 0.02%). This missense change has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 21606396, 22000064, 22214898, 25820315, 27532257, 29178656, 30454721). ClinVar contains an entry for this variant (Variation ID: 466351). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DSG2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Nov 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: SCV001345845.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with cysteine at codon 292 of the DSG2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces arginine with cysteine at codon 292 of the DSG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in homozygous or heterozygous state in individuals affected with arrhythmogenic right ventricular cardiomyopathy; however, it has also been carried by their unaffected relatives (PMID: 21606396, 22000064, 22214898, 25820315, 27532257, 29178656, 30454721, 32877757, 36138163). Two of the affected individuals also carried a pathogenic PKP2 variant, which could explain the disease observed in that individual (PMID: 22214898, 36138163). This variant has also been identified in 12/249360 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The 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. (less)
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Uncertain Significance
(Jan 05, 2024)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004819485.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This missense variant replaces arginine with cysteine at codon 292 of the DSG2 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces arginine with cysteine at codon 292 of the DSG2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in homozygous or heterozygous state in individuals affected with arrhythmogenic right ventricular cardiomyopathy; however, it has also been carried by their unaffected relatives (PMID: 21606396, 22000064, 22214898, 25820315, 27532257, 29178656, 30454721, 32877757). One of the affected individuals also carried a pathogenic PKP2 truncation variant, which could explain the disease observed in that individual (PMID: 22214898). This variant has also been identified in 12/249360 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The 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. (less)
Number of individuals with the variant: 8
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Uncertain significance
(-)
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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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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001921587.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Uncertain significance
(-)
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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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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001930383.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Uncertain significance
(-)
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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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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: SCV001975825.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Likely pathogenic
(Mar 13, 2020)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Arrhythmogenic right ventricular dysplasia 10
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001369731.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS4_Mod,PM2,PP3,PP4. This variant was detected in homozygous state.
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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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Identification and in-silico characterization of splice-site variants from a large cardiogenetic national registry. | Rayani K | European journal of human genetics : EJHG | 2023 | PMID: 36138163 |
Impact of the T-wave characteristics on distinguishing arrhythmogenic right ventricular cardiomyopathy from healthy children. | Imamura T | International journal of cardiology | 2021 | PMID: 32877757 |
A founder homozygous DSG2 variant in East Asia results in ARVC with full penetrance and heart failure phenotype. | Chen L | International journal of cardiology | 2019 | PMID: 30454721 |
Compound and heterozygous mutations of DSG2 identified by Whole Exome Sequencing in arrhythmogenic right ventricular cardiomyopathy/dysplasia with ventricular tachycardia. | Lin Y | Journal of electrocardiology | 2018 | PMID: 30177324 |
Unique genetic background and outcome of non-Caucasian Japanese probands with arrhythmogenic right ventricular dysplasia/cardiomyopathy. | Wada Y | Molecular genetics & genomic medicine | 2017 | PMID: 29178656 |
Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. | Walsh R | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 27532257 |
Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy in the Pediatric Population: Clinical Characterization and Comparison With Adult-Onset Disease. | Te Riele ASJM | JACC. Clinical electrophysiology | 2015 | PMID: 29759408 |
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 |
Compound and digenic heterozygosity in desmosome genes as a cause of arrhythmogenic right ventricular cardiomyopathy in Japanese patients. | Nakajima T | Circulation journal : official journal of the Japanese Circulation Society | 2012 | PMID: 22214898 |
Sudden death during exercise in a juvenile with arrhythmogenic right ventricular cardiomyopathy and desmoglein-2 gene substitution: a case report. | Sato T | Legal medicine (Tokyo, Japan) | 2011 | PMID: 22000064 |
Distinguishing arrhythmogenic right ventricular cardiomyopathy/dysplasia-associated mutations from background genetic noise. | Kapplinger JD | Journal of the American College of Cardiology | 2011 | PMID: 21636032 |
Arrhythmogenic right ventricular dysplasia/cardiomyopathy: pathogenic desmosome mutations in index-patients predict outcome of family screening: Dutch arrhythmogenic right ventricular dysplasia/cardiomyopathy genotype-phenotype follow-up study. | Cox MG | Circulation | 2011 | PMID: 21606396 |
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Text-mined citations for rs770921270 ...
HelpRecord last updated Apr 20, 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.