VCV000016811.15 - ClinVar

NM_001943.5(DSG2):c.918G>A (p.Trp306Ter)

Germline

Classification

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

Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(4); Uncertain significance(1)

6 out of 7 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.918G>A (p.Trp306Ter)

Variation ID: 16811 Accession: VCV000016811.15

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 18q12.1 18: 31524792 (GRCh38) [ NCBI UCSC ] 18: 29104755 (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	Jul 5, 2015	Apr 13, 2025	Jun 3, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001943.5:c.918G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001934.2:p.Trp306Ter	nonsense
NC_000018.10:g.31524792G>A
NC_000018.9:g.29104755G>A
NG_007072.3:g.31551G>A
LRG_397:g.31551G>A
LRG_397t1:c.918G>A	LRG_397p1:p.Trp306Ter

... more HGVS ... less HGVS

Protein change

W306*

Other names

W305*
p.W306*:TGG>TGA

Canonical SPDI

NC_000018.10:31524791:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

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.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Links

ClinGen: CA022354 OMIM: 125671.0002 dbSNP: rs121913007 VarSome

Comment on variant

NCBI staff reviewed the sequence information reported in PubMed 16773573 to determine the location of this allele on current reference sequence.

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	1240	2142

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 (4)	criteria provided, multiple submitters, no conflicts	Apr 29, 2024	RCV000018304.48
not provided	Likely pathogenic (1)	criteria provided, single submitter	Jun 3, 2024	RCV000181248.12
Arrhythmogenic right ventricular dysplasia 10 Dilated cardiomyopathy 1BB	Likely pathogenic (1)	criteria provided, single submitter	Nov 25, 2021	RCV002496397.8
Arrhythmogenic right ventricular cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Dec 18, 2023	RCV003996106.2

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.
Likely pathogenic (Nov 25, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Arrhythmogenic right ventricular dysplasia 10 Dilated cardiomyopathy 1BB Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002807758.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022

Uncertain Significance (Dec 18, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) 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: SCV004842775.1 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)	Publications: PubMed (1) PubMed: 16773573 Comment: This variant changes 1 nucleotide in exon 8 of the DSG2 gene, creating a premature translation stop signal. This variant is expected to result in … (more) This variant changes 1 nucleotide in exon 8 of the DSG2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant (referred to as c.915G>A, W305X) has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy, who also carried another pathogenic variant in the DSG2 gene that could explain the observed phenotype (PMID: 16773573). This variant has been observed in the proband's unaffected mother and sister as well. 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 DSC2 truncation and splice variants in autosomal dominant arrhythmogenic 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

Likely pathogenic (Jun 03, 2024) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000233527.11 First in ClinVar: Jul 05, 2015 Last updated: Sep 16, 2024	Comment: Variant, reported as c.915G>A (W305X) using alternate nomenclature, was observed in the compound heterozygous state with DSG2 p.(R48H) in an individual with ARVC, as well … (more) Variant, reported as c.915G>A (W305X) using alternate nomenclature, was observed in the compound heterozygous state with DSG2 p.(R48H) in an individual with ARVC, as well as in the heterozygous state in two unaffected relatives (PMID: 16773573); Observed in an individual with ARVC (PMID: 31386562); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 20857253, 25525159, 20031617, 31402444, 16773573, 31386562) (less)

Pathogenic (Apr 29, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Arrhythmogenic right ventricular dysplasia 10 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002232679.4 First in ClinVar: Mar 28, 2022 Last updated: Feb 25, 2025	Publications: PubMed (3) PubMed: 17105751‚ 31386562‚ 16773573 Comment: This sequence change creates a premature translational stop signal (p.Trp306) in the DSG2 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Trp306) in the DSG2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DSG2 are known to be pathogenic (PMID: 17105751, 31386562). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with arrhythmogenic right ventricular dysplasia/cardiomyopathy (PMID: 16773573). This variant is also known as W305X. ClinVar contains an entry for this variant (Variation ID: 16811). For these reasons, this variant has been classified as Pathogenic. (less)

Likely pathogenic (Dec 28, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Arrhythmogenic right ventricular dysplasia 10 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002580542.2 First in ClinVar: Oct 15, 2022 Last updated: Apr 13, 2025 Comment: ACMG criteria applied: PVS1, PM2_SUP	Number of individuals with the variant: 2 Sex: female

Likely pathogenic (Mar 14, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Arrhythmogenic right ventricular dysplasia 10 Affected status: yes Allele origin: unknown	KardioGenetik, Herz- und Diabeteszentrum NRW Accession: SCV004809101.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 Comment: PVS1strong, PM2supp, PS4supp; Patient is also carrier of DSG missense variant.	Number of individuals with the variant: 1

Pathogenic (Jul 01, 2006) N Not contributing to aggregate classification	no assertion criteria provided Method: literature only	ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 10 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000038583.5 First in ClinVar: Apr 04, 2013 Last updated: May 13, 2017	Publications: PubMed (1) PubMed: 16773573 Comment on evidence: For discussion of the trp305-to-ter (W305X) mutation in the DSG2 gene that was found in compound heterozygous state in a patient with arrhythmogenic right ventricular … (more) For discussion of the trp305-to-ter (W305X) mutation in the DSG2 gene that was found in compound heterozygous state in a patient with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD10; 610193) by Awad et al. (2006), see 125671.0001. (less)

Comment:

This variant changes 1 nucleotide in exon 8 of the DSG2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant (referred to as c.915G>A, W305X) has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy, who also carried another pathogenic variant in the DSG2 gene that could explain the observed phenotype (PMID: 16773573). This variant has been observed in the proband's unaffected mother and sister as well. 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 DSC2 truncation and splice variants in autosomal dominant arrhythmogenic 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:

Variant, reported as c.915G>A (W305X) using alternate nomenclature, was observed in the compound heterozygous state with DSG2 p.(R48H) in an individual with ARVC, as well as in the heterozygous state in two unaffected relatives (PMID: 16773573); Observed in an individual with ARVC (PMID: 31386562); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 20857253, 25525159, 20031617, 31402444, 16773573, 31386562)

Comment:

This sequence change creates a premature translational stop signal (p.Trp306*) in the DSG2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DSG2 are known to be pathogenic (PMID: 17105751, 31386562). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with arrhythmogenic right ventricular dysplasia/cardiomyopathy (PMID: 16773573). This variant is also known as W305X. ClinVar contains an entry for this variant (Variation ID: 16811). For these reasons, this variant has been classified as Pathogenic.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Arrhythmogenic Right Ventricular Cardiomyopathy-Associated Desmosomal Variants Are Rarely De Novo.	van Lint FHM	Circulation. Genomic and precision medicine	2019	PMID: 31386562
Desmoglein-2 mutations in arrhythmogenic right ventricular cardiomyopathy: a genotype-phenotype characterization of familial disease.	Syrris P	European heart journal	2007	PMID: 17105751
DSG2 mutations contribute to arrhythmogenic right ventricular dysplasia/cardiomyopathy.	Awad MM	American journal of human genetics	2006	PMID: 16773573

Text-mined citations for rs121913007 ...

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 Jun 08, 2025

ClinVar Genomic variation as it relates to human health

NM_001943.5(DSG2):c.918G>A (p.Trp306Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121913007 ...