ClinVar Genomic variation as it relates to human health
NM_001943.5(DSG2):c.1174G>A (p.Val392Ile)
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(1); Benign(8); Likely benign(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001943.5(DSG2):c.1174G>A (p.Val392Ile)
Variation ID: 36009 Accession: VCV000036009.45
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q12.1 18: 31531146 (GRCh38) [ NCBI UCSC ] 18: 29111109 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jul 5, 2015 Apr 15, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001943.5:c.1174G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001934.2:p.Val392Ile missense NC_000018.10:g.31531146G>A NC_000018.9:g.29111109G>A NG_007072.3:g.37905G>A LRG_397:g.37905G>A LRG_397t1:c.1174G>A - Protein change
- V392I
- Other names
- p.V392I:GTC>ATC
- Canonical SPDI
- NC_000018.10:31531145: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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0.00100 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00100
Trans-Omics for Precision Medicine (TOPMed) 0.00142
1000 Genomes Project 30x 0.00156
The Genome Aggregation Database (gnomAD) 0.00158
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00159
The Genome Aggregation Database (gnomAD), exomes 0.00219
Exome Aggregation Consortium (ExAC) 0.00257
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
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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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DSG2 | Some evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1016 | 1757 |
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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Benign (2) |
criteria provided, multiple submitters, no conflicts
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Jul 25, 2018 | RCV000029667.18 | |
Benign/Likely benign (5) |
criteria provided, multiple submitters, no conflicts
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Aug 26, 2019 | RCV000037262.21 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jun 1, 2014 | RCV000148472.13 | |
Benign/Likely benign (6) |
criteria provided, multiple submitters, no conflicts
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Aug 22, 2023 | RCV000472660.30 | |
Likely benign (1) |
criteria provided, single submitter
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Jun 8, 2018 | RCV000619528.10 | |
Benign (1) |
criteria provided, single submitter
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Jan 31, 2024 | RCV001081298.13 | |
Benign (1) |
criteria provided, single submitter
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Jul 25, 2019 | RCV001256759.10 |
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
(Jun 01, 2014)
|
criteria provided, single submitter
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: SCV000190173.2 First in ClinVar: Dec 06, 2014 Last updated: Sep 14, 2015 |
Comment:
Low GERP score may suggest that this variant may belong in a lower pathogenicity class
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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: SCV000060919.5
First in ClinVar: May 03, 2013 Last updated: Apr 09, 2018 |
Comment:
p.Val392Ile in exon 9 of DSG2: This variant has been reported in many individual s with diverse presentations (ARVC, LQTS1, LDAC, DCM: Syrris 2007, Bhuiyan … (more)
p.Val392Ile in exon 9 of DSG2: This variant has been reported in many individual s with diverse presentations (ARVC, LQTS1, LDAC, DCM: Syrris 2007, Bhuiyan 2009, Bauce 2010, Klauke 2010, Quarta 2011, Cox 2011, Bauce 2011, Garcia-Parva 2011, LMM unpublished data). However, this variant has also been identified in 0.7% (1 11/16510) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org;dbSNP rs193922639). In addition, valine (Val) at position 392 is poorly conserved in evolution and the variant is present in two species (including 1 mammal), suggesting that a change to this position may be t olerated. In summary, this variant is likely benign but a modifying role cannot be excluded. (less)
Number of individuals with the variant: 17
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Likely benign
(Jun 28, 2023)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001474568.2
First in ClinVar: Jan 26, 2021 Last updated: Feb 20, 2024 |
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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: SCV000051376.2 First in ClinVar: Jun 08, 2015 Last updated: Sep 14, 2015 |
Number of individuals with the variant: 5
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Benign
(Jun 11, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000902997.1
First in ClinVar: May 20, 2019 Last updated: May 20, 2019 |
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Benign
(Aug 26, 2019)
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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: SCV000697880.2
First in ClinVar: Mar 17, 2018 Last updated: Nov 08, 2019 |
Comment:
Variant summary: DSG2 c.1174G>A (p.Val392Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more)
Variant summary: DSG2 c.1174G>A (p.Val392Ile) 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 0.0022 in 249420 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 200 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSG2 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. Though c.1174G>A has been reported in the literature in individuals affected with ARVC/D, LQTS and DCM, including families showing incomplete co-segregation with disease, in addition, multiple co-occurrences with other pathogenic variants have been noted (PKP2 c.148_151delACAG (p.Thr50fsX61), Bauce_2010, Rigato_2013; PKP2 c.235C>T (p.Arg79X), Cox _2011), providing supporting evidence for a benign role. Publication also reported experimental evidence evaluating an impact on protein function, and demonstrated no damaging effect of this variant (Gaertner_2012, Dieding_2017). Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as Benign (2x), Likely benign (3x) or VUS (1x). Based on the evidence outlined above, the variant was classified as benign. (less)
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Benign
(Jul 25, 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: SCV000901998.2
First in ClinVar: May 06, 2019 Last updated: May 31, 2020 |
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Benign
(Jul 25, 2019)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular dysplasia 1
Affected status: yes
Allele origin:
germline
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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV001433191.1
First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020 |
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Likely benign
(Jun 08, 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: SCV000734934.4
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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Benign
(Sep 08, 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: SCV000233494.7
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 23812740, 26899768, 25637381, 23299917, 21636032, 24070718, 17105751, 20031616, 20129281, 20829228, 21606390, 21859740, 21606396, 21723241, 23071725, 23396983, … (more)
This variant is associated with the following publications: (PMID: 23812740, 26899768, 25637381, 23299917, 21636032, 24070718, 17105751, 20031616, 20129281, 20829228, 21606390, 21859740, 21606396, 21723241, 23071725, 23396983, 24436435, 24055113, 26138720, 26681313, 27153395, 25985138, 28255936, 29062102, 30885746) (less)
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Benign
(Aug 22, 2023)
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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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Mendelics
Accession: SCV001135117.2
First in ClinVar: Jan 09, 2020 Last updated: Aug 25, 2023 |
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Benign
(Jan 31, 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: SCV000561397.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
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Benign
(Sep 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004140913.4
First in ClinVar: Nov 20, 2023 Last updated: Apr 15, 2024 |
Comment:
DSG2: BP4, BS1, BS2
Number of individuals with the variant: 2
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
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: SCV001924013.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
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: SCV001929572.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
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: SCV001959098.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Likely benign
(-)
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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: SCV001965704.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Likely benign
(-)
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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: SCV001739689.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 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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Arrhythmogenic cardiomyopathy related DSG2 mutations affect desmosomal cadherin binding kinetics. | Dieding M | Scientific reports | 2017 | PMID: 29062102 |
Genetic basis of familial dilated cardiomyopathy patients undergoing heart transplantation. | Cuenca S | The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation | 2016 | PMID: 26899768 |
Phenotypic expression is a prerequisite for malignant arrhythmic events and sudden cardiac death in arrhythmogenic right ventricular cardiomyopathy. | Zorzi 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: 26138720 |
Does p.Q247X in TRIM63 cause human hypertrophic cardiomyopathy? | Ploski R | Circulation research | 2014 | PMID: 24436435 |
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 |
TMEM43 mutations associated with arrhythmogenic right ventricular cardiomyopathy in non-Newfoundland populations. | Baskin B | Human genetics | 2013 | PMID: 23812740 |
In vitro functional analyses of arrhythmogenic right ventricular cardiomyopathy-associated desmoglein-2-missense variations. | Gaertner A | PloS one | 2012 | PMID: 23071725 |
Desmosomal protein gene mutations in patients with idiopathic dilated cardiomyopathy undergoing cardiac transplantation: a clinicopathological study. | Garcia-Pavia P | Heart (British Cardiac Society) | 2011 | PMID: 21859740 |
Clinical phenotype and diagnosis of arrhythmogenic right ventricular cardiomyopathy in pediatric patients carrying desmosomal gene mutations. | Bauce B | Heart rhythm | 2011 | PMID: 21723241 |
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 |
Familial evaluation in arrhythmogenic right ventricular cardiomyopathy: impact of genetics and revised task force criteria. | Quarta G | Circulation | 2011 | PMID: 21606390 |
De novo desmin-mutation N116S is associated with arrhythmogenic right ventricular cardiomyopathy. | Klauke B | Human molecular genetics | 2010 | PMID: 20829228 |
Multiple mutations in desmosomal proteins encoding genes in arrhythmogenic right ventricular cardiomyopathy/dysplasia. | Bauce B | Heart rhythm | 2010 | PMID: 20129281 |
Desmoglein-2 and desmocollin-2 mutations in dutch arrhythmogenic right ventricular dysplasia/cardiomypathy patients: results from a multicenter study. | Bhuiyan ZA | Circulation. Cardiovascular genetics | 2009 | PMID: 20031616 |
Desmoglein-2 mutations in arrhythmogenic right ventricular cardiomyopathy: a genotype-phenotype characterization of familial disease. | Syrris P | European heart journal | 2007 | PMID: 17105751 |
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Text-mined citations for rs193922639 ...
HelpRecord last updated Apr 15, 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.