ClinVar Genomic variation as it relates to human health
NM_024422.6(DSC2):c.631-2A>G
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.
Pathogenic(3); Likely pathogenic(4); Uncertain significance(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_024422.6(DSC2):c.631-2A>G
Variation ID: 16850 Accession: VCV000016850.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q12.1 18: 31087815 (GRCh38) [ NCBI UCSC ] 18: 28667778 (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 Apr 4, 2013 Apr 20, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_024422.6:c.631-2A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NM_001406506.1:c.202-2A>G splice acceptor NM_001406507.1:c.202-2A>G splice acceptor NM_004949.5:c.631-2A>G splice acceptor NC_000018.10:g.31087815T>C NC_000018.9:g.28667778T>C NG_008208.2:g.19611A>G LRG_400:g.19611A>G LRG_400t1:c.631-2A>G - Protein change
- Other names
- IVS5AS, A-G, -2
- Canonical SPDI
- NC_000018.10:31087814:T:C
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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.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
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
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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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DSC2 | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1560 | 1695 |
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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Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV000018344.35 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Sep 7, 2022 | RCV000181140.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 28, 2023 | RCV001183801.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 8, 2023 | RCV003338383.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 1, 2023 | RCV003996109.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 15, 2019 | RCV004017258.1 |
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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Likely pathogenic
(-)
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criteria provided, single submitter
Method: research
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Arrhythmogenic right ventricular cardiomyopathy, type 11
Affected status: no
Allele origin:
germline
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UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill
Study: NSIGHT-NC NEXUS
Accession: SCV001251504.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant alters a canonical splice acceptor site in DSC2. This variant has been described previously in the heterozygous state in a patient with autosomal … (more)
This variant alters a canonical splice acceptor site in DSC2. This variant has been described previously in the heterozygous state in a patient with autosomal dominant arrhythmogenic right ventricular cardiomyopathy (PMID: 17186466). (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Dec 09, 2022)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular dysplasia 11
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV003835899.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
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Likely pathogenic
(Sep 08, 2023)
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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: SCV004058107.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The c.631-2A>G intronic variant results from an A to G substitution two nucleotides before from coding exon 6 in the DSC2 gene. This variant has … (more)
The c.631-2A>G intronic variant results from an A to G substitution two nucleotides before from coding exon 6 in the DSC2 gene. This variant has been detected in an individual from an arrhythmogenic right ventricular cardiomyopathy (ARVC) cohort with limited clinical detail, and in an individual reported to meet ARVC diagnostic criteria (Baskin B et al. Hum Genet, 2013 Nov;132:1245-52; Heuser A et al. Am J Hum Genet, 2006 Dec;79:1081-8). This variant has also been detected in several cohorts without known ARVC; however, clinical details were often limited (Mazzarotto F et al. Genet Med, 2021 05;23:856-864; Carruth ED et al. Circ Genom Precis Med, 2021 04;14:e003302; Lacaze P et al. NPJ Genom Med, 2021 Jun;6:51; van Rooij J et al. Genet Med, 2020 11;22:1812-1820; Roman TS et al. Am J Hum Genet, 2020 10;107:596-611; Gierman HJ et al. PLoS One, 2014 Nov;9:e112430). In RNA studies by one group, this alteration resulted in aberrant splicing due to use of a cryptic donor site resulting in a frameshift and premature truncation (Heuser A et al. Am J Hum Genet, 2006 Dec;79:1081-8). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. (less)
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Pathogenic
(Dec 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular dysplasia 11
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002021763.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Uncertain Significance
(Dec 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial isolated arrhythmogenic right ventricular dysplasia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004822987.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This variant alters the canonical splice acceptor site in intron 5 of the DSC2 gene. Computational splicing tools predict that this variant may disrupt splicing. … (more)
This variant alters the canonical splice acceptor site in intron 5 of the DSC2 gene. Computational splicing tools predict that this variant may disrupt splicing. This variant has been reported in two individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 17186466, 23812740). This variant has also been identified in 4/251040 chromosomes in the general population by the Genome Aggregation Database (gnomAD), as well as in a supercentenarian (110 years or older) (PMID: 25390934). Quantitative real-time PCR in cardiac tissue biopsy of an affected individual has shown that this variant leads to aberrant splicing and reduced DSC2 protein levels (PMID: 17186466). Splice and other loss-of-function DSC2 variants have been observed in individuals affected with arrhythmogenic right ventricular cardiomyopathy. Although there is a suspicion for a pathogenic role, clinical significance of loss-of-function DSC2 variants in autosomal dominant arrhythmogenic cardiomyopathy is not yet clearly established. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 5
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Uncertain Significance
(Aug 15, 2019)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000063121.6
First in ClinVar: May 03, 2013 Last updated: Apr 20, 2024 |
Comment:
The c.631-2A>G variant in DSC2 has been reported in 2 individuals with ARVC and 1 individual with LVNC (Heuser 2006, LMM data). It was also … (more)
The c.631-2A>G variant in DSC2 has been reported in 2 individuals with ARVC and 1 individual with LVNC (Heuser 2006, LMM data). It was also reported in a 110-year-old individual (Gierman 2014) and in ClinVar (Variation ID: 16850). This variant has been identified in 4/111556 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence, and in vitro studies confirmed that it leads to aberrant splicing and reduced DSC2 protein levels (Heuser 2006). Splice and other loss-of-function variants in DSC2 have been reported in individuals with ARVC; however, the clinical significance of these variants is not yet fully understood. Although ARVC has primarily been described as a dominant disorder, in several reports of loss-of function variants, only those individuals with a variant on the second allele were affected, suggesting that LOF variants may either act in a recessive manner or have a much milder effect than missense variants. In summary, while there is some suspicion for a pathogenic role in the heterozygous state, the clinical significance of the c.631-2A>G variant, with regard to dominant ARVC is uncertain. ACMG/AMP Criteria applied: PS4_Supporting, PM2, PS3_Moderate. (less)
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Likely pathogenic
(Dec 01, 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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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502809.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
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Pathogenic
(Sep 07, 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: SCV000233417.11
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; … (more)
Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32466575, 25390934, 33684294, 32853555, 31402444, 32665702, 23812740, 31872082, 34135346, 33087929, 29788292, 33500567, 17186466) (less)
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Pathogenic
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular dysplasia 11
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000950273.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects an acceptor splice site in intron 5 of the DSC2 gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects an acceptor splice site in intron 5 of the DSC2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DSC2 are known to be pathogenic (PMID: 23911551). This variant is present in population databases (rs397514042, gnomAD 0.004%). Disruption of this splice site has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 17186466). ClinVar contains an entry for this variant (Variation ID: 16850). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 17186466). For these reasons, this variant has been classified as Pathogenic. (less)
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Uncertain significance
(Feb 28, 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: SCV001349628.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant alters the canonical splice acceptor site in intron 5 of the DSC2 gene. Computational splicing tools predict that this variant may disrupt splicing. … (more)
This variant alters the canonical splice acceptor site in intron 5 of the DSC2 gene. Computational splicing tools predict that this variant may disrupt splicing. This variant has been reported in two individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 17186466, 23812740). This variant has also been identified in 4/251040 chromosomes in the general population by the Genome Aggregation Database (gnomAD), as well as in a supercentenarian (110 years or older) (PMID: 25390934). Quantitative real-time PCR in cardiac tissue biopsy of an affected individual has shown that this variant leads to aberrant splicing and reduced DSC2 protein levels (PMID: 17186466). Splice and other loss-of-function DSC2 variants have been observed in individuals affected with arrhythmogenic right ventricular cardiomyopathy. Although there is a suspicion for a pathogenic role, clinical significance of loss-of-function DSC2 variants in autosomal dominant arrhythmogenic cardiomyopathy is not yet clearly established. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Pathogenic
(Dec 01, 2006)
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no assertion criteria provided
Method: literature only
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ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 11
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000038623.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a 58-year-old male patient with arrhythmogenic right ventricular cardiomyopathy (ARVD11; 610476), Heuser et al. (2006) observed a heterozygous splice acceptor site mutation in intron … (more)
In a 58-year-old male patient with arrhythmogenic right ventricular cardiomyopathy (ARVD11; 610476), Heuser et al. (2006) observed a heterozygous splice acceptor site mutation in intron 5 of the DSC2 gene: 631-2A-G. The mutation led to the use of a cryptic splice acceptor site and the creation of a downstream premature termination codon. (less)
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Pathogenic
(-)
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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: SCV001952497.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
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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: SCV001972196.1 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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Genetic variants associated with inherited cardiovascular disorders among 13,131 asymptomatic older adults of European descent. | Lacaze P | NPJ genomic medicine | 2021 | PMID: 34135346 |
Clinical Findings and Diagnostic Yield of Arrhythmogenic Cardiomyopathy Through Genomic Screening of Pathogenic or Likely Pathogenic Desmosome Gene Variants. | Carruth ED | Circulation. Genomic and precision medicine | 2021 | PMID: 33684294 |
Systematic large-scale assessment of the genetic architecture of left ventricular noncompaction reveals diverse etiologies. | Mazzarotto F | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 33500567 |
Exome sequencing and characterization of 49,960 individuals in the UK Biobank. | Van Hout CV | Nature | 2020 | PMID: 33087929 |
Genomic Sequencing for Newborn Screening: Results of the NC NEXUS Project. | Roman TS | American journal of human genetics | 2020 | PMID: 32853555 |
Reduced penetrance of pathogenic ACMG variants in a deeply phenotyped cohort study and evaluation of ClinVar classification over time. | van Rooij J | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 32665702 |
Reevaluation of genetic variants previously associated with arrhythmogenic right ventricular cardiomyopathy integrating population-based cohorts and proteomics data. | Ye JZ | Clinical genetics | 2019 | PMID: 31402444 |
Whole-genome sequencing of the world's oldest people. | Gierman HJ | PloS one | 2014 | PMID: 25390934 |
Mechanistic basis of desmosome-targeted diseases. | Al-Jassar C | Journal of molecular biology | 2013 | PMID: 23911551 |
TMEM43 mutations associated with arrhythmogenic right ventricular cardiomyopathy in non-Newfoundland populations. | Baskin B | Human genetics | 2013 | PMID: 23812740 |
Review on the genetics of arrhythmogenic right ventricular dysplasia. | Moric-Janiszewska E | 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 | 2007 | PMID: 17363426 |
Mutant desmocollin-2 causes arrhythmogenic right ventricular cardiomyopathy. | Heuser A | American journal of human genetics | 2006 | PMID: 17186466 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
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Text-mined citations for rs397514042 ...
HelpRecord last updated Jun 10, 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.