This sequence change affects the initiator methionine of the DSG2 mRNA. The next in-frame methionine is located at codon 179. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 17105751, 20829228). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 657863). This variant disrupts the p.Arg49 amino acid residue in DSG2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19151369). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_001943.5(DSG2):c.3G>A (p.Met1Ile)
Germline
Classification
Help
criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.
Conflicting classifications of pathogenicity
Pathogenic(2); Likely pathogenic(3); Uncertain significance(2)
Pathogenic(2); Likely pathogenic(3); Uncertain significance(2)
7 out of 7 submissions contributed to this classification
Help
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.
7
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001943.5(DSG2):c.3G>A (p.Met1Ile)
Variation ID: 657863 Accession: VCV000657863.31
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q12.1 18: 31498254 (GRCh38) [ NCBI UCSC ] 18: 29078217 (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 Aug 14, 2019 Feb 25, 2025 Nov 16, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001943.5:c.3G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001934.2:p.Met1Ile missense initiator codon variant NC_000018.10:g.31498254G>A NC_000018.9:g.29078217G>A NG_007072.3:g.5013G>A LRG_397:g.5013G>A LRG_397t1:c.3G>A - Protein change
- M1I
- Other names
- -
- Canonical SPDI
- NC_000018.10:31498253: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
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
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. |
|||
| DSG2 | Some evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1219 | 2106 | |
| LOC130062340 | - | - | - | GRCh38 | - | 109 |
Conditions - Germline
| Condition
Help
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
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
May 14, 2024 | RCV002223950.19 | |
| Conflicting classifications of pathogenicity (3) |
criteria provided, conflicting classifications
|
Nov 16, 2024 | RCV000814563.11 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Oct 2, 2023 | RCV004001763.2 |
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
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Nov 16, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Arrhythmogenic right ventricular dysplasia 10
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000954976.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 25, 2025 |
Comment:
This sequence change affects the initiator methionine of the DSG2 mRNA. The next in-frame methionine is located at codon 179. This variant is not present … (more)
This sequence change affects the initiator methionine of the DSG2 mRNA. The next in-frame methionine is located at codon 179. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 17105751, 20829228). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 657863). This variant disrupts the p.Arg49 amino acid residue in DSG2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19151369). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Likely pathogenic
(Jul 12, 2019)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Arrhythmogenic right ventricular dysplasia 10
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001369398.3
First in ClinVar: Jul 04, 2020 Last updated: Sep 03, 2023 |
Comment:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2.
|
|
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Pathogenic
(Aug 11, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002503576.2
First in ClinVar: Apr 23, 2022 Last updated: Sep 03, 2023 |
Number of individuals with the variant: 1
Secondary finding: no
|
|
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Uncertain Significance
(Oct 02, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Arrhythmogenic right ventricular cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004838837.1
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)
|
Comment:
This variant alters methionine at codon 1 of the DSG2 mRNA that serves as the translation initiation codon. An alternate in-frame methionine downstream of the … (more)
This variant alters methionine at codon 1 of the DSG2 mRNA that serves as the translation initiation codon. An alternate in-frame methionine downstream of the initiator methionine occurs at codon 179 in extracellular cadherin domain 2, after signal peptide and propeptide. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two siblings affected with arrhythmogenic right ventricular cardiomyopathy, along with a second missense variant of uncertain significance in the same gene (PMID: 20829228), and in an individual with unspecified phenotype (PMID: 33968641). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, clinical relevance of loss-of-function DSG2 variants in autosomal dominant arrhythmogenic right ventricular cardiomyopathy is not yet clearly established. 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: 1
Zygosity: Single Heterozygote
|
|
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Uncertain significance
(Jun 05, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Arrhythmogenic right ventricular dysplasia 10
Affected status: yes
Allele origin:
unknown
|
KardioGenetik, Herz- und Diabeteszentrum NRW
Accession: SCV005094557.1
First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
Comment:
PVS1_moderate, PS4_supporting, PM2_supporting
Number of individuals with the variant: 1
|
|
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Likely pathogenic
(May 14, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV005414953.1
First in ClinVar: Nov 30, 2024 Last updated: Nov 30, 2024 |
Comment:
Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Reported in patients with ARVC in published literature … (more)
Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Reported in patients with ARVC in published literature but detailed clinical information was not included (PMID: 36264615); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20829228, 36264615) (less)
|
|
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Likely pathogenic
(May 01, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002546000.18
First in ClinVar: Jul 09, 2022 Last updated: Dec 22, 2024 |
Comment:
DSG2: PM2, PS1:Moderate, PVS1:Moderate, PS4:Supporting
Number of individuals with the variant: 1
|
Comment:
Comment:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2.
Comment:
This variant alters methionine at codon 1 of the DSG2 mRNA that serves as the translation initiation codon. An alternate in-frame methionine downstream of the initiator methionine occurs at codon 179 in extracellular cadherin domain 2, after signal peptide and propeptide. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two siblings affected with arrhythmogenic right ventricular cardiomyopathy, along with a second missense variant of uncertain significance in the same gene (PMID: 20829228), and in an individual with unspecified phenotype (PMID: 33968641). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, clinical relevance of loss-of-function DSG2 variants in autosomal dominant arrhythmogenic right ventricular cardiomyopathy is not yet clearly established. 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.
Comment:
PVS1_moderate, PS4_supporting, PM2_supporting
Comment:
Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Reported in patients with ARVC in published literature but detailed clinical information was not included (PMID: 36264615); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20829228, 36264615)
Comment:
DSG2: PM2, PS1:Moderate, PVS1:Moderate, PS4:Supporting
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. |
Comment:
This sequence change affects the initiator methionine of the DSG2 mRNA. The next in-frame methionine is located at codon 179. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 17105751, 20829228). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 657863). This variant disrupts the p.Arg49 amino acid residue in DSG2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19151369). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2.
Comment:
This variant alters methionine at codon 1 of the DSG2 mRNA that serves as the translation initiation codon. An alternate in-frame methionine downstream of the initiator methionine occurs at codon 179 in extracellular cadherin domain 2, after signal peptide and propeptide. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two siblings affected with arrhythmogenic right ventricular cardiomyopathy, along with a second missense variant of uncertain significance in the same gene (PMID: 20829228), and in an individual with unspecified phenotype (PMID: 33968641). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, clinical relevance of loss-of-function DSG2 variants in autosomal dominant arrhythmogenic right ventricular cardiomyopathy is not yet clearly established. 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.
Comment:
PVS1_moderate, PS4_supporting, PM2_supporting
Comment:
Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Reported in patients with ARVC in published literature but detailed clinical information was not included (PMID: 36264615); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20829228, 36264615)
Comment:
DSG2: PM2, PS1:Moderate, PVS1:Moderate, PS4:Supporting
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Actionable secondary findings in arrhythmogenic right ventricle cardiomyopathy genes: impact and challenge of genetic counseling. | Abicht A | Cardiovascular diagnosis and therapy | 2021 | PMID: 33968641 |
| De novo desmin-mutation N116S is associated with arrhythmogenic right ventricular cardiomyopathy. | Klauke B | Human molecular genetics | 2010 | PMID: 20829228 |
| 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 |
| Desmoglein-2 mutations in arrhythmogenic right ventricular cardiomyopathy: a genotype-phenotype characterization of familial disease. | Syrris P | European heart journal | 2007 | PMID: 17105751 |
Text-mined citations for rs1021457619 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Feb 26, 2025
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.