ClinVar Genomic variation as it relates to human health
NM_001943.5(DSG2):c.1912G>A (p.Gly638Arg)
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(7); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001943.5(DSG2):c.1912G>A (p.Gly638Arg)
Variation ID: 161224 Accession: VCV000161224.34
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q12.1 18: 31541225 (GRCh38) [ NCBI UCSC ] 18: 29121188 (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 7, 2014 Apr 20, 2024 Jan 22, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001943.5:c.1912G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001934.2:p.Gly638Arg missense NC_000018.10:g.31541225G>A NC_000018.9:g.29121188G>A NG_007072.3:g.47984G>A LRG_397:g.47984G>A LRG_397t1:c.1912G>A - Protein change
- G638R
- Other names
- p.G638R:GGA>AGA
- Canonical SPDI
- NC_000018.10:31541224: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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00017
The Genome Aggregation Database (gnomAD) 0.00016
Trans-Omics for Precision Medicine (TOPMed) 0.00011
Exome Aggregation Consortium (ExAC) 0.00012
The Genome Aggregation Database (gnomAD), exomes 0.00013
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
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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DSG2 | Some evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1092 | 1881 |
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
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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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Dec 18, 2023 | RCV000148474.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 7, 2016 | RCV000154703.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 22, 2024 | RCV000539539.8 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 5, 2022 | RCV000619011.2 | |
Uncertain significance (6) |
criteria provided, single submitter
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Oct 21, 2022 | RCV000766866.9 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Feb 16, 2023 | RCV001170377.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 27, 2021 | RCV002492540.1 |
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
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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Uncertain significance
(Nov 07, 2016)
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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: SCV000204382.4
First in ClinVar: Jan 31, 2015 Last updated: Apr 09, 2018 |
Comment:
The p.Gly638Arg variant in DSG2 has been identified in 1 Caucasian individual wi th HCM (LMM data) and at least 1 Caucasian individual with ARVC/D … (more)
The p.Gly638Arg variant in DSG2 has been identified in 1 Caucasian individual wi th HCM (LMM data) and at least 1 Caucasian individual with ARVC/D (De Bortoli 2 010, Rigato 2013). Although the variant segregated with disease in one affected sibling, it was also identified in 2 apparently unaffected older siblings (De Bo rtoli 2010, Rigato 2013). This variant has been identified in 14/66666 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs201564919). Computational prediction tools and conservation analy sis suggest that the p.Gly638Arg variant may impact the protein, though this inf ormation is not predictive enough to determine pathogenicity. In summary, the cl inical significance of the p.Gly638Arg variant is uncertain. (less)
Number of individuals with the variant: 2
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Uncertain significance
(May 15, 2019)
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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: SCV001332952.2
First in ClinVar: May 31, 2020 Last updated: Jan 01, 2022 |
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Likely benign
(Jan 05, 2022)
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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: SCV000737779.4
First in ClinVar: Apr 14, 2018 Last updated: Nov 29, 2022 |
Comment:
This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, … (more)
This alteration is classified as likely benign based on a combination of the following: 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)
Number of individuals with the variant: 1
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Uncertain significance
(Aug 27, 2021)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular dysplasia 10
Dilated cardiomyopathy 1BB
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002797675.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Oct 21, 2022)
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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: SCV000233506.13
First in ClinVar: Jan 31, 2015 Last updated: Mar 04, 2023 |
Comment:
Reported in conjunction with additional cardiogenetic variants in individuals with ARVC or sudden death (De Bortoli et al., 2010; Bauce et al., 2011; Rigato et … (more)
Reported in conjunction with additional cardiogenetic variants in individuals with ARVC or sudden death (De Bortoli et al., 2010; Bauce et al., 2011; Rigato et al., 2013; Sanchez et al., 2016; El-Battrawy et al., 2018); Identified in a patient with Brugada syndrome in published literature (Di Resta et al., 2015); Identified independently and in conjunction with additional variants in individuals referred for cardiac genetic testing at GeneDx; segregation data is limited at this time; 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: 25637381, 24070718, 23299917, 21723241, 27930701, 29566126, 33803477, 34300226, 32050722, 20197793, 31402444, 26220970) (less)
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Uncertain significance
(Feb 16, 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: SCV001350806.4
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces glycine with arginine at codon 638 of the DSG2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces glycine with arginine at codon 638 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). This variant was reported in one individual affected with arrhythmogenic right ventricular cardiomyopathy and in three unaffected individuals from a family (PMID: 20197793) and an individual affected with sudden death (PMID: 27930701). It has been shown that this variant segregates with disease in four related individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 29566126). Cardiomyocytes from one of these heterozygous carriers have shown ion channel dysfunctions and abnormal cellular electrophysiology as well as enhanced sensitivity to adrenergic stimulation (PMID: 29566126). This variant has also been identified in 33/280710 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 22, 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: SCV000641967.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 638 of the DSG2 protein (p.Gly638Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 638 of the DSG2 protein (p.Gly638Arg). This variant is present in population databases (rs201564919, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of DSG2-related conditions (PMID: 20197793, 26220970, 27930701, 35819174). ClinVar contains an entry for this variant (Variation ID: 161224). 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
(Dec 18, 2023)
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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: SCV004819585.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This missense variant replaces glycine with arginine at codon 638 of the DSG2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces glycine with arginine at codon 638 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). This variant was reported in one individual affected with arrhythmogenic right ventricular cardiomyopathy and in three unaffected individuals from a family (PMID: 20197793) and an individual affected with sudden death (PMID: 27930701). It has been shown that this variant segregates with disease in four related individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 29566126). Cardiomyocytes from one of these heterozygous carriers have shown ion channel dysfunctions and abnormal cellular electrophysiology as well as enhanced sensitivity to adrenergic stimulation (PMID: 29566126). This variant has also been identified in 33/280710 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: 44
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Uncertain significance
(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
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CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190175.1 First in ClinVar: Dec 07, 2014 Last updated: Dec 07, 2014 |
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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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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001740923.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 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, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001918954.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 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: SCV001932557.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 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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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: SCV001952498.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 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: SCV001968852.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 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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Burden of rare variants in arrhythmogenic cardiomyopathy with right dominant form-associated genes provides new insights for molecular diagnosis and clinical management. | Goudal A | Human mutation | 2022 | PMID: 35819174 |
Electrical dysfunctions in human-induced pluripotent stem cell-derived cardiomyocytes from a patient with an arrhythmogenic right ventricular cardiomyopathy. | El-Battrawy I | 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 | 2018 | PMID: 29566126 |
Natural and Undetermined Sudden Death: Value of Post-Mortem Genetic Investigation. | Sanchez O | PloS one | 2016 | PMID: 27930701 |
High-throughput genetic characterization of a cohort of Brugada syndrome patients. | Di Resta C | Human molecular genetics | 2015 | PMID: 26220970 |
Actionable exomic incidental findings in 6503 participants: challenges of variant classification. | Amendola LM | Genome research | 2015 | PMID: 25637381 |
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 |
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 |
The p.A897KfsX4 frameshift variation in desmocollin-2 is not a causative mutation in arrhythmogenic right ventricular cardiomyopathy. | De Bortoli M | European journal of human genetics : EJHG | 2010 | PMID: 20197793 |
Text-mined citations for rs201564919 ...
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.