ClinVar Genomic variation as it relates to human health
NM_001943.5(DSG2):c.1562A>G (p.Asp521Gly)
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.1562A>G (p.Asp521Gly)
Variation ID: 180320 Accession: VCV000180320.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q12.1 18: 31536340 (GRCh38) [ NCBI UCSC ] 18: 29116303 (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 Feb 7, 2015 May 1, 2024 Nov 15, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001943.5:c.1562A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001934.2:p.Asp521Gly missense NC_000018.10:g.31536340A>G NC_000018.9:g.29116303A>G NG_007072.3:g.43099A>G LRG_397:g.43099A>G LRG_397t1:c.1562A>G - Protein change
- D521G
- Other names
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- Canonical SPDI
- NC_000018.10:31536339:A:G
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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) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
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 |
1110 | 1917 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Jun 26, 2023 | RCV000157185.4 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Mar 7, 2023 | RCV000539173.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 3, 2023 | RCV001181773.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 15, 2023 | RCV004019894.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Apr 03, 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: SCV001346995.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces aspartic acid with glycine at codon 521 of the DSG2 protein. Computational prediction suggests that this variant may have a deleterious … (more)
This missense variant replaces aspartic acid with glycine at codon 521 of the DSG2 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with arrhythmogenic right ventricular cardiomyopathy or dysplasia (PMID: 29178656). This variant has been identified in 5/249444 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
(Mar 07, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000641964.4
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
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 … (more)
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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DSG2 protein function. ClinVar contains an entry for this variant (Variation ID: 180320). This missense change has been observed in individual(s) with DSG2-related conditions (PMID: 29178656). This variant is present in population databases (rs730880077, gnomAD 0.02%). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 521 of the DSG2 protein (p.Asp521Gly). (less)
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Uncertain Significance
(Jun 26, 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: SCV004819562.1
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 missense variant replaces aspartic acid with glycine at codon 521 of the DSG2 protein. Computational prediction suggests that this variant may have a deleterious … (more)
This missense variant replaces aspartic acid with glycine at codon 521 of the DSG2 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with arrhythmogenic right ventricular cardiomyopathy or dysplasia (PMID: 29178656). This variant has been identified in 5/249444 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: 2
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Uncertain significance
(Nov 15, 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: SCV005018364.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
The p.D521G variant (also known as c.1562A>G), located in coding exon 11 of the DSG2 gene, results from an A to G substitution at nucleotide … (more)
The p.D521G variant (also known as c.1562A>G), located in coding exon 11 of the DSG2 gene, results from an A to G substitution at nucleotide position 1562. The aspartic acid at codon 521 is replaced by glycine, an amino acid with similar properties. This variant co-occurred with other DSG2 variants in individuals from an arrhythmogenic right ventricular cardiomyopathy (ARVC) cohort (Wada Y et al. Mol Genet Genomic Med, 2017 Nov;5:639-651). This variant was also detected in a sudden death case with features of ARVC (Takahashi Y et al. Int J Legal Med, 2023 Nov;137:1927-1937). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Mar 16, 2017)
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criteria provided, single submitter
Method: research
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Arrhythmogenic right ventricular cardiomyopathy
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Agnes Ginges Centre for Molecular Cardiology, Centenary Institute
Accession: SCV001156268.1
First in ClinVar: Feb 07, 2020 Last updated: Feb 07, 2020 |
Comment:
The DSG2 Asp521Gly is absent in the 1000 genomes project (http://www.1000genomes.org/), and present at low frequency in the Exome Aggregation Consortium dataset (MAF=0.000025; http://exac.broadinstitute.org/). We … (more)
The DSG2 Asp521Gly is absent in the 1000 genomes project (http://www.1000genomes.org/), and present at low frequency in the Exome Aggregation Consortium dataset (MAF=0.000025; http://exac.broadinstitute.org/). We identified this variant in a HCM patient with no family history of disease or SCD. Computational tools SIFT, MutationTaster, and PolyPhen-2 predict the variant to have a deleterious effect. In summary, while this is a rare variant, there is currently no evidence that DSG2 can cause an HCM phenotype, therefore we classify DSG2 Asp521Gly as a variant of "uncertain significance". (less)
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Uncertain significance
(Jan 13, 2018)
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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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Illumina Laboratory Services, Illumina
Accession: SCV001286953.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
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Uncertain significance
(Oct 14, 2014)
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no assertion criteria provided
Method: clinical testing
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Arrhythmogenic right ventricular cardiomyopathy
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV000206909.1
First in ClinVar: Feb 07, 2015 Last updated: Feb 07, 2015 |
Number of individuals with the variant: 1
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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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Postmortem genetic analysis of 17 sudden cardiac deaths identified nonsense and frameshift variants in two cases of arrhythmogenic cardiomyopathy. | Takahashi Y | International journal of legal medicine | 2023 | PMID: 37328711 |
Unique genetic background and outcome of non-Caucasian Japanese probands with arrhythmogenic right ventricular dysplasia/cardiomyopathy. | Wada Y | Molecular genetics & genomic medicine | 2017 | PMID: 29178656 |
Text-mined citations for rs730880077 ...
HelpRecord last updated Sep 29, 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.