ClinVar Genomic variation as it relates to human health
NM_001943.5(DSG2):c.523+2T>C
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.523+2T>C
Variation ID: 44321 Accession: VCV000044321.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q12.1 18: 31521245 (GRCh38) [ NCBI UCSC ] 18: 29101208 (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 1, 2016 Feb 14, 2024 Jan 10, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001943.5:c.523+2T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NC_000018.10:g.31521245T>C NC_000018.9:g.29101208T>C NG_007072.3:g.28004T>C LRG_397:g.28004T>C LRG_397t1:c.523+2T>C - Protein change
- Other names
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- Canonical SPDI
- NC_000018.10:31521244: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
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD), exomes 0.00001
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 |
1016 | 1757 |
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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Likely pathogenic (1) |
criteria provided, single submitter
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Feb 21, 2018 | RCV000037309.7 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 4, 2023 | RCV000181206.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 10, 2023 | RCV000232524.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 15, 2020 | RCV000241644.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 18, 2021 | RCV002477091.1 |
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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Pathogenic
(Jun 15, 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: SCV000320191.6
First in ClinVar: Oct 02, 2016 Last updated: Nov 29, 2022 |
Comment:
The c.523+2T>C intronic pathogenic mutation results from a T to C substitution two nucleotides after coding exon 5 of the DSG2 gene. This alteration has … (more)
The c.523+2T>C intronic pathogenic mutation results from a T to C substitution two nucleotides after coding exon 5 of the DSG2 gene. This alteration has been previously reported in several patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), sometimes in conjunction with other ARVC variants (Fressart V, Europace 2010 Jun; 12(6):861-8; Tan BY, J Cardiovasc Transl Res 2010 Dec; 3(6):663-73). This variant has also been detected in a sudden infant death syndrome cohort (Tester DJ et al. J. Am. Coll. Cardiol., 2018 03;71:1217-1227). 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 a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Sep 18, 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: SCV002777468.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely pathogenic
(Feb 21, 2018)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular cardiomyopathy
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000060966.5
First in ClinVar: May 03, 2013 Last updated: Apr 09, 2018 |
Comment:
The c.523+2T>C variant in DSG2 has been reported in 6 individuals with clinical features of arrhythmogenic right ventricular cardiomyopathy (ARVC; Fressart 2010 , Tan 2010, … (more)
The c.523+2T>C variant in DSG2 has been reported in 6 individuals with clinical features of arrhythmogenic right ventricular cardiomyopathy (ARVC; Fressart 2010 , Tan 2010, LMM unpublished data). This variant has been identified in 2/105830 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.b roadinstitute.org; dbSNP rs397516709) and reported in ClinVar (Variation ID 4432 1). c.523+2T>C variant occurs in the invariant region (+/- 1,2) of the splice co nsensus sequence and is predicted to cause altered splicing leading to an abnorm al or absent protein. Heterozygous loss of function of the DSG2 gene has been im plicated in ARVC. In summary, although additional studies are required to fully establish its clinical significance, the c.523+2T>C variant is likely pathogenic . ACMG/AMP Criteria applied: PM2; PVS1_Moderate; PS4_Moderate. (less)
Number of individuals with the variant: 5
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Pathogenic
(Jul 12, 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: SCV002503398.1
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
(Jan 04, 2023)
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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: SCV000233484.13
First in ClinVar: Jul 05, 2015 Last updated: Apr 01, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant predicted to result in a null allele in a gene for … (more)
Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 20400443, 26314686, 25525159, 20857253, 23671136, 23889974, 23810894, 28588093, 28471438, 25820315, 30790397, 30122538, 29544605, 31386562, 31402444, 31589614, 33232181, 33238575) (less)
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Pathogenic
(Jan 10, 2023)
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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: SCV000287244.7
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
Comment:
This variant is present in population databases (rs397516709, gnomAD 0.002%). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the … (more)
This variant is present in population databases (rs397516709, gnomAD 0.002%). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 44321). Disruption of this splice site has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 2040044, 20857253). This sequence change affects a donor splice site in intron 5 of the DSG2 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 DSG2 are known to be pathogenic (PMID: 17105751, 31386562). (less)
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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 Right Ventricular Cardiomyopathy-Associated Desmosomal Variants Are Rarely De Novo. | van Lint FHM | Circulation. Genomic and precision medicine | 2019 | PMID: 31386562 |
Cardiac Genetic Predisposition in Sudden Infant Death Syndrome. | Tester DJ | Journal of the American College of Cardiology | 2018 | PMID: 29544605 |
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 |
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
Mutation-positive arrhythmogenic right ventricular dysplasia/cardiomyopathy: the triangle of dysplasia displaced. | Te Riele AS | Journal of cardiovascular electrophysiology | 2013 | PMID: 23889974 |
Incremental value of cardiac magnetic resonance imaging in arrhythmic risk stratification of arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated desmosomal mutation carriers. | te Riele AS | Journal of the American College of Cardiology | 2013 | PMID: 23810894 |
Risk stratification in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated desmosomal mutation carriers. | Bhonsale A | Circulation. Arrhythmia and electrophysiology | 2013 | PMID: 23671136 |
Shared desmosome gene findings in early and late onset arrhythmogenic right ventricular dysplasia/cardiomyopathy. | Tan BY | Journal of cardiovascular translational research | 2010 | PMID: 20857253 |
Desmosomal gene analysis in arrhythmogenic right ventricular dysplasia/cardiomyopathy: spectrum of mutations and clinical impact in practice. | Fressart V | 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 | 2010 | PMID: 20400443 |
Desmoglein-2 mutations in arrhythmogenic right ventricular cardiomyopathy: a genotype-phenotype characterization of familial disease. | Syrris P | European heart journal | 2007 | PMID: 17105751 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Long-term results after balloon pulmonary valvuloplasty. | McCrindle BW | Circulation | 1991 | PMID: 2040044 |
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Text-mined citations for rs397516709 ...
HelpRecord last updated Feb 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.