VCV000576810.14 - ClinVar

NM_001943.5(DSG2):c.2817del (p.Tyr940fs)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(1); Uncertain significance(1)

3 out of 3 submissions contributed to this classification

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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001943.5(DSG2):c.2817del (p.Tyr940fs)

Variation ID: 576810 Accession: VCV000576810.14

Type and length

Deletion, 1 bp

Location

Cytogenetic: 18q12.1 18: 31546202 (GRCh38) [ NCBI UCSC ] 18: 29126165 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Oct 10, 2018	Feb 25, 2025	Jul 8, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_001943.5:c.2817del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001934.2:p.Tyr940fs	frameshift
NC_000018.10:g.31546203del
NC_000018.9:g.29126166del
NG_007072.3:g.52962del
LRG_397:g.52962del
LRG_397t1:c.2817del

... more HGVS ... less HGVS

Protein change

Y940fs

Other names

Canonical SPDI

NC_000018.10:31546201:CC:C

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA891843561 dbSNP: rs1567934773 VarSome

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
Gene	OMIM	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	1283	2221
DSG2-AS1	-	-	-	GRCh38	-	811

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.
Arrhythmogenic right ventricular dysplasia 10	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jul 8, 2022	RCV000699399.17
Cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Dec 4, 2019	RCV001192101.11

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.	Expand all rows Collapse all rows 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.
Likely pathogenic (Aug 06, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Arrhythmogenic right ventricular dysplasia/cardiomyopathy, type 10	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine Accession: SCV001434979.1 First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020	Comment: show The frameshift variant, c.2817delC (p.Tyr940Metfs*12) in the DSG2 gene is predicted to introduce a premature translation termination codon. It has not been seen in the general population according to the gnomAD database. Loss of function could be the mechanism for DSG2 protein (PMID 23911551, 23381804). Therefore, this variant is classified as likely pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Dec 04, 2019) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	Color Diagnostics, LLC DBA Color Health Accession: SCV001360076.2 First in ClinVar: Jun 22, 2020 Last updated: Jan 15, 2022	Comment: show This variant deletes 1 nucleotide in exon 15 of the DSG2 gene, creating a frameshift and premature translation stop signal in the last exon. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Clinical significance of loss-of-function truncation variants in the DSG2 gene is not 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) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Platform type: NGS

Pathogenic (Jul 08, 2022) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Arrhythmogenic right ventricular dysplasia 10	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000828106.5 First in ClinVar: Oct 10, 2018 Last updated: Feb 25, 2025	Publications: PubMed (4) PubMed: 28492532‚ 20864495‚ 21397041‚ 23381804 Comment: show This variant disrupts a region of the DSG2 protein in which other variant(s) (p.Glu1020Alafs18) have been determined to be pathogenic (PMID: 20864495, 21397041, 23381804). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This sequence change creates a premature translational stop signal (p.Tyr940Metfs12) in the DSG2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 179 amino acid(s) of the DSG2 protein. This variant is not present in population databases (gnomAD no frequency). 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: 576810). For these reasons, this variant has been classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

The frameshift variant, c.2817delC (p.Tyr940Metfs*12) in the DSG2 gene is predicted to introduce a premature translation termination codon. It has not been seen in the general population according to the gnomAD database. Loss of function could be the mechanism for DSG2 protein (PMID 23911551, 23381804). Therefore, this variant is classified as likely pathogenic.

Comment:

This variant deletes 1 nucleotide in exon 15 of the DSG2 gene, creating a frameshift and premature translation stop signal in the last exon. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Clinical significance of loss-of-function truncation variants in the DSG2 gene is not 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:

This variant disrupts a region of the DSG2 protein in which other variant(s) (p.Glu1020Alafs*18) have been determined to be pathogenic (PMID: 20864495, 21397041, 23381804). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This sequence change creates a premature translational stop signal (p.Tyr940Metfs*12) in the DSG2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 179 amino acid(s) of the DSG2 protein. This variant is not present in population databases (gnomAD no frequency). 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: 576810). For these reasons, this variant has been classified as Pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Mutated desmoglein-2 proteins are incorporated into desmosomes and exhibit dominant-negative effects in arrhythmogenic right ventricular cardiomyopathy.	Rasmussen TB	Human mutation	2013	PMID: 23381804
Population-prevalent desmosomal mutations predisposing to arrhythmogenic right ventricular cardiomyopathy.	Lahtinen AM	Heart rhythm	2011	PMID: 21397041
Wide spectrum of desmosomal mutations in Danish patients with arrhythmogenic right ventricular cardiomyopathy.	Christensen AH	Journal of medical genetics	2010	PMID: 20864495

Text-mined citations for rs1567934773 ...

These 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 Jul 28, 2025