ClinVar Genomic variation as it relates to human health
NM_001943.5(DSG2):c.716T>C (p.Val239Ala)
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(3); 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.716T>C (p.Val239Ala)
Variation ID: 44326 Accession: VCV000044326.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q12.1 18: 31524473 (GRCh38) [ NCBI UCSC ] 18: 29104436 (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 Jan 31, 2015 May 1, 2024 Jan 30, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001943.5:c.716T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001934.2:p.Val239Ala missense NC_000018.10:g.31524473T>C NC_000018.9:g.29104436T>C NG_007072.3:g.31232T>C LRG_397:g.31232T>C LRG_397t1:c.716T>C - Protein change
- V239A
- Other names
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- Canonical SPDI
- NC_000018.10:31524472: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.
Exome Aggregation Consortium (ExAC) 0.00009
The Genome Aggregation Database (gnomAD), exomes 0.00009
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00025
Trans-Omics for Precision Medicine (TOPMed) 0.00032
The Genome Aggregation Database (gnomAD) 0.00037
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 |
1100 | 1895 |
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
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
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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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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jun 26, 2023 | RCV000037314.7 | |
Likely benign (1) |
criteria provided, single submitter
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Jul 20, 2020 | RCV000621582.4 | |
Uncertain significance (2) |
criteria provided, single submitter
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Mar 7, 2023 | RCV000766364.7 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 30, 2024 | RCV001086638.7 | |
Uncertain significance (1) |
criteria provided, single submitter
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- | RCV001293112.1 | |
Likely benign (1) |
criteria provided, single submitter
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Feb 21, 2020 | RCV001186663.2 |
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
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
(May 31, 2012)
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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: SCV000060971.5
First in ClinVar: May 03, 2013 Last updated: Jan 31, 2015 |
Comment:
The Val239Ala variant in DSG2 has been reported in 1 individual with ARVC and wa s absent from 600 control chromosomes (Quarta 2011). This variant … (more)
The Val239Ala variant in DSG2 has been reported in 1 individual with ARVC and wa s absent from 600 control chromosomes (Quarta 2011). This variant has also been identified in 2/3136 African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS). Valine (Val) at position 239 is highly conserved in mammal and evolutionarily distant specie s, though computational analyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to t he protein. Additional information is needed to fully assess the clinical signif icance of the Val239Ala variant. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Mar 07, 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: SCV000566926.6
First in ClinVar: May 02, 2019 Last updated: Jul 08, 2023 |
Comment:
Reported in at least one individual meeting task force criteria for ARVC in published literature (Quarta et al., 2011); In silico analysis supports that this … (more)
Reported in at least one individual meeting task force criteria for ARVC in published literature (Quarta et al., 2011); 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: 23299917, 31402444, 21606390) (less)
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Likely benign
(Feb 21, 2020)
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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: SCV001353202.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
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Uncertain significance
(-)
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criteria provided, single submitter
Method: research
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Primary dilated cardiomyopathy
Affected status: yes
Allele origin:
unknown
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Genetics and Genomics Program, Sidra Medicine
Accession: SCV001434102.1
First in ClinVar: Feb 28, 2021 Last updated: Feb 28, 2021 |
Number of individuals with the variant: 1
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Likely benign
(Jun 26, 2023)
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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: SCV004020861.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
Variant summary: DSG2 c.716T>C (p.Val239Ala) results in a non-conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Five of … (more)
Variant summary: DSG2 c.716T>C (p.Val239Ala) results in a non-conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 280460 control chromosomes (gnomAD), predominantly at a frequency of 0.0012 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSG2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (0.00025), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.716T>C has been reported in the literature in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (e.g. Quarta_2011), Dilated Cardiomyopathy (e.g. Seidelmann_2017, Al-Shafai_2021) and in a stillborn infant (Seidelmann_2017). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30615648, 28087566, 21606390, 34137518). Five ClinVar submitters have assessed the variant since 2014: two classified the variant as uncertain significance and three as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Likely benign
(Jan 30, 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: SCV000551012.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 14, 2024 |
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Likely benign
(Jul 20, 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: SCV000734921.5
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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)
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Uncertain significance
(May 11, 2016)
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no assertion criteria provided
Method: provider interpretation
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not provided
Affected status: unknown
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000924772.1
First in ClinVar: Jun 29, 2019 Last updated: Jun 29, 2019 |
Comment:
p.Val239Ala (c.716T>C) in DSG2 (NM_001943.3) We have seen this variant in a patient with a TIA at a young age and a family history of … (more)
p.Val239Ala (c.716T>C) in DSG2 (NM_001943.3) We have seen this variant in a patient with a TIA at a young age and a family history of early stroke, sudden death, and cardiomyopathy. We did not see evidence of ARVC in the family though only minimal data is available on the relative with cardiomyopathy and sudden death. Given the frequency in the general population, we consider this variant a variant of uncertain significance, probably benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Per the lab report, the variant has been reported in at least one case of ARVC (Quarta et al 2011). Per the lab report, "Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies." Per the lab report, "This variant is present in population databases (rs200997703, ExAC 0.1%)." (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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Genetic evaluation of cardiomyopathies in Qatar identifies enrichment of pathogenic sarcomere gene variants and possible founder disease mutations in the Arabs. | Al-Shafai KN | Molecular genetics & genomic medicine | 2021 | PMID: 34137518 |
In vitro analysis of arrhythmogenic cardiomyopathy associated desmoglein-2 (DSG2) mutations reveals diverse glycosylation patterns. | Debus JD | Journal of molecular and cellular cardiology | 2019 | PMID: 30885746 |
Identification of putative pathogenic single nucleotide variants (SNVs) in genes associated with heart disease in 290 cases of stillbirth. | Sahlin E | PloS one | 2019 | PMID: 30615648 |
Frequency of genetic variants associated with arrhythmogenic right ventricular cardiomyopathy in the genome aggregation database. | Hall CL | European journal of human genetics : EJHG | 2018 | PMID: 29802319 |
Application of Whole Exome Sequencing in the Clinical Diagnosis and Management of Inherited Cardiovascular Diseases in Adults. | Seidelmann SB | Circulation. Cardiovascular genetics | 2017 | PMID: 28087566 |
Molecular and cytogenetic analysis in stillbirth: results from 481 consecutive cases. | Sahlin E | Fetal diagnosis and therapy | 2014 | PMID: 25059832 |
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 |
Familial evaluation in arrhythmogenic right ventricular cardiomyopathy: impact of genetics and revised task force criteria. | Quarta G | Circulation | 2011 | PMID: 21606390 |
Text-mined citations for rs200997703 ...
HelpRecord last updated May 01, 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.