ClinVar Genomic variation as it relates to human health
NM_001943.5(DSG2):c.875G>A (p.Arg292His)
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.875G>A (p.Arg292His)
Variation ID: 44330 Accession: VCV000044330.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q12.1 18: 31524749 (GRCh38) [ NCBI UCSC ] 18: 29104712 (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 Dec 19, 2017 May 1, 2024 Feb 5, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001943.5:c.875G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001934.2:p.Arg292His missense NC_000018.10:g.31524749G>A NC_000018.9:g.29104712G>A NG_007072.3:g.31508G>A LRG_397:g.31508G>A LRG_397t1:c.875G>A - Protein change
- R292H
- Other names
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- Canonical SPDI
- NC_000018.10:31524748: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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0.00020 (A)
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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00007
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Trans-Omics for Precision Medicine (TOPMed) 0.00022
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 |
1100 | 1896 |
Conditions - Germline
Condition
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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
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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 (1) |
criteria provided, single submitter
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Jan 17, 2018 | RCV000037318.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 17, 2024 | RCV000205277.7 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Nov 22, 2023 | RCV000770549.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 18, 2021 | RCV000767197.10 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 5, 2024 | RCV003996325.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 13, 2022 | RCV004018835.1 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Mar 15, 2022 | RCV002490507.2 |
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
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
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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
(Oct 09, 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: SCV002779796.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Jan 13, 2022)
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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: SCV004859464.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
The c.875G>A (p.R292H) alteration is located in exon 8 (coding exon 8) of the DSG2 gene. This alteration results from a G to A substitution … (more)
The c.875G>A (p.R292H) alteration is located in exon 8 (coding exon 8) of the DSG2 gene. This alteration results from a G to A substitution at nucleotide position 875, causing the arginine (R) at amino acid position 292 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Mar 15, 2022)
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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:
germline
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New York Genome Center
Accession: SCV003925213.1
First in ClinVar: May 20, 2023 Last updated: May 20, 2023 |
Comment:
The c.875G>A variant identified in DSG2 has previously been reported in the literature in individuals with ARVC/D either in trans with another variant [PMID: 25172079] … (more)
The c.875G>A variant identified in DSG2 has previously been reported in the literature in individuals with ARVC/D either in trans with another variant [PMID: 25172079] or heterozygous [PMID: 31702781], and it has been deposited in ClinVar as variant of uncertain significance by multiple submitters [ClinVar ID:44330]. The c.875G>A variant is observed in 58 alleles (~0.01% MAF with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases which may also include individuals with cardiac phenotypes. The c.875G>A variant is located in exon 8 of this 15-exon gene, and predicted to replace an evolutionarily conserved arginine amino acid with histidine at position 292 within the extracellular domain of the encoded protein. In silico predictions are inconclusive of the variant's effect [(CADD v1.6 = 25, REVEL = 0.313)]; however, thereare no functional studies to support or refute these predictions. Another variant affecting the same codon (c.874C>T:p.(Arg292Cys)) has also been reported in the literature [PMID: 28349240] and ClinVar [ClinVar ID: 466351] as variant of uncertain significance. Based on available evidence this c.875G>Ap.(Arg292His) variant identified in DSG2 is classified as a Variant of Uncertain Significance. (less)
Clinical Features:
Right ventricular cardiomyopathy (present)
Secondary finding: no
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Uncertain significance
(Jul 21, 2022)
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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
Study: Canadian Open Genetics Repository
Accession: SCV000901996.2 First in ClinVar: May 06, 2019 Last updated: Feb 04, 2024 |
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Uncertain significance
(Jan 17, 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: SCV000261997.7
First in ClinVar: Jan 31, 2016 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 292 of the DSG2 protein (p.Arg292His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 292 of the DSG2 protein (p.Arg292His). This variant is present in population databases (rs185821167, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with DSG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 44330). 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) performed at Invitae indicates that this missense variant is not expected to disrupt DSG2 protein function with a negative predictive value of 95%. 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. (less)
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Uncertain significance
(Jan 17, 2018)
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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: SCV000060975.5
First in ClinVar: May 03, 2013 Last updated: Apr 09, 2018 |
Comment:
proposed classification - variant undergoing re-assessment, contact laboratory
Number of individuals with the variant: 2
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Uncertain significance
(Jun 18, 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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GeneDx
Accession: SCV000622048.4
First in ClinVar: Dec 19, 2017 Last updated: Mar 04, 2023 |
Comment:
Reported in several patients with ARVC who also harbor a second potentially disease-causing variant in the DSG2 gene (Segura-Rodriguez et al., 2020); Reported in ClinVar … (more)
Reported in several patients with ARVC who also harbor a second potentially disease-causing variant in the DSG2 gene (Segura-Rodriguez et al., 2020); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 44330; Landrum et al., 2016); 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: 25172079, 31702781, 27535533, 21606396, 26383259) (less)
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Uncertain significance
(Nov 22, 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: SCV001735670.2
First in ClinVar: Jun 19, 2021 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with histidine at codon 292 of the DSG2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces arginine with histidine at codon 292 of the DSG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in the homozygous state in several individuals affected with arrhythmogenic right ventricular cardiomyopathy/dysplasia and in the heterozygous state in their unaffected relatives (PMID: 25172079, 31702781). This variant has also been identified in 24/280756 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
(Feb 05, 2024)
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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: SCV004819486.1
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 arginine with histidine at codon 292 of the DSG2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces arginine with histidine at codon 292 of the DSG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in the homozygous state in several individuals affected with arrhythmogenic right ventricular cardiomyopathy/dysplasia and in the heterozygous state in their unaffected relatives (PMID: 25172079, 31702781). This variant has also been identified in 24/280756 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: 26
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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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Myocardial fibrosis in arrhythmogenic cardiomyopathy: a genotype-phenotype correlation study. | Segura-Rodríguez D | European heart journal. Cardiovascular Imaging | 2020 | PMID: 31702781 |
A recessive inheritance pattern contributes to arrhythmogenic biventricular cardiomyopathy. | Jiménez-Jáimez J | Revista espanola de cardiologia (English ed.) | 2014 | PMID: 25172079 |
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 |
Text-mined citations for rs185821167 ...
HelpRecord last updated May 08, 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.