ClinVar Genomic variation as it relates to human health
NM_001943.5(DSG2):c.146G>A (p.Arg49His)
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.146G>A (p.Arg49His)
Variation ID: 16810 Accession: VCV000016810.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q12.1 18: 31519867 (GRCh38) [ NCBI UCSC ] 18: 29099830 (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 7, 2017 Apr 20, 2024 Dec 11, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001943.5:c.146G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001934.2:p.Arg49His missense NC_000018.10:g.31519867G>A NC_000018.9:g.29099830G>A NG_007072.3:g.26626G>A LRG_397:g.26626G>A LRG_397t1:c.146G>A LRG_397p1:p.Arg49His Q14126:p.Arg49His - Protein change
- R49H
- Other names
- p.R49H:CGC>CAC
- p.R49H
- Canonical SPDI
- NC_000018.10:31519866: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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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
- Comment on variant
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 |
1092 | 1881 |
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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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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May 17, 2023 | RCV000018303.40 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 11, 2023 | RCV000211715.14 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 17, 2020 | RCV000181198.15 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 3, 2022 | RCV002254518.9 |
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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Pathogenic
(Dec 17, 2020)
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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: SCV000233476.10
First in ClinVar: Jul 05, 2015 Last updated: Apr 17, 2019 |
Comment:
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Functional studies show R49H abolishes pro-peptide cleavage and affects desmosomal adhesiveness … (more)
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Functional studies show R49H abolishes pro-peptide cleavage and affects desmosomal adhesiveness (Vite et al., 2020); 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: 29237690, 23671136, 19151369, 20152563, 16773573, 20400443, 27532257, 28283360, 19863551, 25820315, 20031617, 20857253, 31447099, 31845994, 32268277, 31645976, 30790397, 32356610, 31402444) (less)
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Pathogenic
(May 17, 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: SCV002224220.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
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) … (more)
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: 16810). This variant is also known as R48H. This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 19151369, 19863551, 20400443). In at least one individual the variant was observed to be de novo. This variant is present in population databases (rs121913006, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 49 of the DSG2 protein (p.Arg49His). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 11, 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: SCV004822556.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This c.146G>A (p.Arg49His) variant in the DSG2 gene has previously been reported in a 41 y/o patient with ARVD/cardiomyopathy [PMID 19151369]. Both parents were negative … (more)
This c.146G>A (p.Arg49His) variant in the DSG2 gene has previously been reported in a 41 y/o patient with ARVD/cardiomyopathy [PMID 19151369]. Both parents were negative for the change, suggesting that this variant arises de novo in the patient. This variant was also reported in a 42 y/o patient with ARVD/cardiomyopathy (reported as p.Arg48His in PMID 16773573]. The patient was compound heterozygous for p.Trp305* and p.Arg48His. The p.Trp305* was inherited from the asymptomatic mother and also present in one sibling, also asymptomatic. The father was not available for testing. The variant is located in the propeptide domain, in the furin cleavage site and is hypothesized to disrupt the production of the mature protein. This variant has been observed in one heterozygous individual from the ExAC database (http://exac.broadinstitute.org/variant/18-29099830-G-A). Arginine at position 49 of the DSG2 protein is highly conserved. While not clinically validated, computer-based algorithms SIFT and Polyphen2 predict this p.Arg49His change to be deleterious. It is thus interpreted as a pathogenic variant. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jun 06, 2017)
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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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Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV000839951.1
First in ClinVar: May 13, 2017 Last updated: May 13, 2017 |
Comment:
This c.146G>A (p.Arg49His) variant in the DSG2 gene has previously been reported in a 41 y/o patient with ARVD cardiomyopathy [PMID 19151369]. Both parents were … (more)
This c.146G>A (p.Arg49His) variant in the DSG2 gene has previously been reported in a 41 y/o patient with ARVD cardiomyopathy [PMID 19151369]. Both parents were negative for the change, suggesting that this variant arises de novo in the patient. This variant was also reported in a 42 y/o patient with ARVD cardiomyopathy (reported as p.Arg48His in PMID 16773573]. The patient was compound heterozygous for p.Trp305* and p.Arg48His. The trp305* was inherited from the asymptomatic mother and also present in one sibling, also asymptomatic. The father was not available for testing. The variant is located in the propeptide domain, in the furin cleavage site and is hypothesized to disrupt the production of the mature protein. This variant has been observed in one heterozygous individual from the ExAC database (http://exac.broadinstitute.org/variant/18-29099830-G-A). Arginine at position 49 of the DSG2 protein is highly conserved. While not clinically validated, computer-based algorithms SIFT and Polyphen2 predict this p.Arg49His change to be deleterious. It is thus interpreted as a pathogenic variant. (less)
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Likely pathogenic
(Jan 31, 2019)
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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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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000060922.6
First in ClinVar: May 03, 2013 Last updated: Apr 09, 2018 |
Comment:
The p.Arg49His variant in DSG2 has been reported in > 10 individuals with clinical features of ARVC, including 1 de novo and 2 compound heterozygous … (more)
The p.Arg49His variant in DSG2 has been reported in > 10 individuals with clinical features of ARVC, including 1 de novo and 2 compound heterozygous occurrences (Awad 2006, den Haan 2009, Gandjbakhch 2009, Fressart 2010, Barahona-Dussault 2010, Tan 2010, Xu 2010, Gaido 2017, Walsh 2017). Additionally, the variant segregated with disease in 2 affected relatives from 1 family (Gaido, 2017). This variant has also been reported in ClinVar (Variation ID 16810) and has been identified in 1/113204 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis suggest that the p.Arg49His variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg49His variant is likely pathogenic. ACMG/ AMP Criteria applied: PS2, PM2, PS4_Moderate, PP3. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jun 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Arrhythmogenic right ventricular dysplasia 9
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations
Accession: SCV002522687.1
First in ClinVar: Jun 18, 2022 Last updated: Jun 18, 2022 |
Comment:
We observed a rare c.146G>A (p.R49H) genetic variant in the DSG2 gene in a 19-y.o. male proband, diagnosed with arrhythmogenic right ventricular cardiomyopathy (definite diagnosis). … (more)
We observed a rare c.146G>A (p.R49H) genetic variant in the DSG2 gene in a 19-y.o. male proband, diagnosed with arrhythmogenic right ventricular cardiomyopathy (definite diagnosis). ClinVar contains an entry for this variant (Variation ID: 16810) observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 16773573‚ 19151369‚ 20152563‚ 20400443‚ 19863551‚ 20031617‚ 23671136‚ 28283360‚ 25820315‚ 20857253). Online bioinformatic resources classify the c.146G>A (p.R49H) variant as probably pathogenic. The p.R49H variant predicted to abolish a cleavage motif Arg-X-Lys-Arg (RXKR) in desmoglein, disrupting production of mature, functional protein (Awad et al., 2006). Functional studies show the c.146G>A (p.R49H) variant abolishes pro-peptide cleavage and affects desmosomal adhesiveness (Vite et al., 2020). For these reasons, this variant has been classified as Pathogenic. (less)
Age: 10-19 years
Sex: male
Ethnicity/Population group: Russian
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Pathogenic
(Jul 01, 2006)
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no assertion criteria provided
Method: literature only
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ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 10
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000038582.4
First in ClinVar: Apr 04, 2013 Last updated: May 13, 2017 |
Comment on evidence:
In a patient with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD10; 610193), Awad et al. (2006) found compound heterozygosity for mutations in the DSG2 gene. One was … (more)
In a patient with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD10; 610193), Awad et al. (2006) found compound heterozygosity for mutations in the DSG2 gene. One was a G-to-A transition at nucleotide 134 in exon 3, which results in the substitution of a conserved arginine with histidine (R48H). These arginines occur as the first and fourth amino acids within the RXKR furin-cleavage motif. The second mutation present in the patient of Awad et al. (2006) was a 915G-A transition in exon 8 resulting in premature termination at codon trp305 (W305X; 125671.0002). The W305X mutation was present in heterozygous state in the unaffected sister and mother of the proband with compound heterozygosity. Awad et al. (2006) suggested that this may indicate incomplete penetrance or that the W305X mutation is insufficient to result in ARVD/C in isolation. Because the mutation creates a premature termination codon, mutant transcripts were predicted to be rapidly degraded by the nonsense-mediated mRNA decay (NMD) pathway. This would then suggest that haploinsufficiency for desmoglein-2 is not the mechanism for disease. The patient had structural and functional right ventricular abnormality, ECG depolarization abnormality, ECG repolarization abnormality, and diagnostic arrhythmias. (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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Phenotypic expression of ARVC: How 12 lead ECG can predict left or right ventricle involvement. A familiar case series and a review of literature. | Gaido L | International journal of cardiology | 2017 | PMID: 28283360 |
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 |
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 |
Compound and digenic heterozygosity contributes to arrhythmogenic right ventricular cardiomyopathy. | Xu T | Journal of the American College of Cardiology | 2010 | PMID: 20152563 |
Role of genetic testing in arrhythmogenic right ventricular cardiomyopathy/dysplasia. | Barahona-Dussault C | Clinical genetics | 2010 | PMID: 19863551 |
Comprehensive desmosome mutation analysis in north americans with arrhythmogenic right ventricular dysplasia/cardiomyopathy. | den Haan AD | Circulation. Cardiovascular genetics | 2009 | PMID: 20031617 |
Sporadic arrhythmogenic right ventricular cardiomyopathy/dysplasia due to a de novo mutation. | Gandjbakhch 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 | 2009 | PMID: 19151369 |
DSG2 mutations contribute to arrhythmogenic right ventricular dysplasia/cardiomyopathy. | Awad MM | American journal of human genetics | 2006 | PMID: 16773573 |
Text-mined citations for rs121913006 ...
HelpRecord last updated Apr 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.
NCBI staff reviewed the sequence information reported in PubMed 16773573 to determine the location of this allele on current reference sequence.