ClinVar Genomic variation as it relates to human health
NM_001943.5(DSG2):c.136C>T (p.Arg46Trp)
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.136C>T (p.Arg46Trp)
Variation ID: 863095 Accession: VCV000863095.6
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q12.1 18: 31519857 (GRCh38) [ NCBI UCSC ] 18: 29099820 (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 Apr 15, 2020 Feb 14, 2024 Aug 20, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001943.5:c.136C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001934.2:p.Arg46Trp missense NC_000018.10:g.31519857C>T NC_000018.9:g.29099820C>T NG_007072.3:g.26616C>T LRG_397:g.26616C>T LRG_397t1:c.136C>T - Protein change
- R46W
- Other names
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- Canonical SPDI
- NC_000018.10:31519856:C:T
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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
- Links
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 |
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 (1) |
criteria provided, single submitter
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Aug 20, 2023 | RCV001069981.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 18, 2022 | RCV002379620.1 |
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
(Apr 18, 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: SCV002702243.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.R46W pathogenic mutation (also known as c.136C>T), located in coding exon 3 of the DSG2 gene, results from a C to T substitution at … (more)
The p.R46W pathogenic mutation (also known as c.136C>T), located in coding exon 3 of the DSG2 gene, results from a C to T substitution at nucleotide position 136. The arginine at codon 46 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been identified in multiple individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC); however, clinical details were limited for some cases (Fressart V et al. Europace, 2010 Jun;12:861-8; Vite A et al. PLoS ONE, 2013 Sep;8:e75082; Philips B et al. Circ Arrhythm Electrophysiol, 2014 Apr;7:230-6; Walsh R et al. Genet. Med., 2017 02;19:192-203; Wada Y et al. Mol Genet Genomic Med, 2017 11;5:639-651; Chen K et al. Clin Cardiol, 2018 May;41:615-622; Ruiz Salas A et al. Rev Esp Cardiol (Engl Ed). 2018 Dec;71(12):1018-1026; Hermida A et al. Eur J Heart Fail. 2019 06;21(6):792-800; Invitae pers. comm.). Another alteration at the same codon, p.R46Q (c.137G>A), has also been reported in association with ARVC and has shown segregation with disease (Awad MM et al. Am J Hum Genet, 2006 Jul;79:136-42; Rasmussen TB et al. Hum Mutat, 2013 May;34:697-705). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Aug 20, 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: SCV001235186.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 46 of the DSG2 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 46 of the DSG2 protein (p.Arg46Trp). This variant is present in population databases (rs752522753, gnomAD 0.003%). This missense change has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 20400443, 24585727, 27532257, 29178656, 30790397, 31386562; Invitae). ClinVar contains an entry for this variant (Variation ID: 863095). For these reasons, this variant has been classified as Pathogenic. 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. This variant disrupts the p.Arg46 amino acid residue in DSG2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23071725, 30790397). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. (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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Desmoglein-2 mutations in propeptide cleavage-site causes arrhythmogenic right ventricular cardiomyopathy/dysplasia by impairing extracellular 1-dependent desmosomal interactions upon cellular stress. | Vite A | 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 | 2020 | PMID: 31845994 |
Arrhythmogenic Right Ventricular Cardiomyopathy-Associated Desmosomal Variants Are Rarely De Novo. | van Lint FHM | Circulation. Genomic and precision medicine | 2019 | PMID: 31386562 |
High risk of heart failure associated with desmoglein-2 mutations compared to plakophilin-2 mutations in arrhythmogenic right ventricular cardiomyopathy/dysplasia. | Hermida A | European journal of heart failure | 2019 | PMID: 30790397 |
Absence of a primary role for TTN missense variants in arrhythmogenic cardiomyopathy: From a clinical and pathological perspective. | Chen K | Clinical cardiology | 2018 | PMID: 29750433 |
Usefulness of Genetic Study by Next-generation Sequencing in High-risk Arrhythmogenic Cardiomyopathy. | Ruiz Salas A | Revista espanola de cardiologia (English ed.) | 2018 | PMID: 29606362 |
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 |
Remodelling of myocardial intercalated disc protein connexin 43 causes increased susceptibility to malignant arrhythmias in ARVC/D patients. | Chen X | Forensic science international | 2017 | PMID: 28288337 |
Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. | Walsh R | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 27532257 |
Arrhythmogenic right ventricular dysplasia/cardiomyopathy and cardiac sarcoidosis: distinguishing features when the diagnosis is unclear. | Philips B | Circulation. Arrhythmia and electrophysiology | 2014 | PMID: 24585727 |
Desmosomal cadherins are decreased in explanted arrhythmogenic right ventricular dysplasia/cardiomyopathy patient hearts. | Vite A | PloS one | 2013 | PMID: 24086444 |
In vitro functional analyses of arrhythmogenic right ventricular cardiomyopathy-associated desmoglein-2-missense variations. | Gaertner A | PloS one | 2012 | PMID: 23071725 |
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 |
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Text-mined citations for rs752522753 ...
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.