NM_001943.5(DSG2):c.3040G>A (p.Val1014Ile) AND Arrhythmogenic right ventricular cardiomyopathy

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 11, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003996319.2

Allele description [Variation Report for NM_001943.5(DSG2):c.3040G>A (p.Val1014Ile)]

NM_001943.5(DSG2):c.3040G>A (p.Val1014Ile)

Genes:

DSG2-AS1:DSG2 antisense RNA 1 [Gene - HGNC]
DSG2:desmoglein 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

18q12.1

Genomic location:

Preferred name:

NM_001943.5(DSG2):c.3040G>A (p.Val1014Ile)

Other names:

p.V1014I:GTC>ATC

HGVS:

NC_000018.10:g.31546426G>A
NG_007072.3:g.53185G>A
NM_001943.5:c.3040G>AMANE SELECT
NP_001934.2:p.Val1014Ile
LRG_397t1:c.3040G>A
LRG_397:g.53185G>A
NC_000018.9:g.29126389G>A
NM_001943.3:c.3040G>A
NM_001943.4:c.3040G>A
c.3040G>A

Protein change:

V1014I

Links:

dbSNP: rs200830807

NCBI 1000 Genomes Browser:

rs200830807

Molecular consequence:

NM_001943.5:c.3040G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Arrhythmogenic right ventricular cardiomyopathy (ARVD)
Synonyms:: Cardiomyopathy, ARVC; Arrhythmogenic right ventricular dysplasia
Identifiers:: MONDO: MONDO:0016587; MeSH: D019571; MedGen: C0349788

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004821866	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jan 11, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 20716751, 23861362, 24503780, 27114410, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004821866

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Jan 11, 2024)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	29	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Prevalence of desmosomal protein gene mutations in patients with dilated cardiomyopathy.

Elliott P, O'Mahony C, Syrris P, Evans A, Rivera Sorensen C, Sheppard MN, Carr-White G, Pantazis A, McKenna WJ.

Circ Cardiovasc Genet. 2010 Aug;3(4):314-22. doi: 10.1161/CIRCGENETICS.110.937805.

PubMed [citation]

PMID:: 20716751

Interpreting secondary cardiac disease variants in an exome cohort.

Ng D, Johnston JJ, Teer JK, Singh LN, Peller LC, Wynter JS, Lewis KL, Cooper DN, Stenson PD, Mullikin JC, Biesecker LG; NIH Intramural Sequencing Center (NISC) Comparative Sequencing Program.

Circ Cardiovasc Genet. 2013 Aug;6(4):337-46. doi: 10.1161/CIRCGENETICS.113.000039. Epub 2013 Jul 16.

PubMed [citation]

PMID:: 23861362
PMCID:: PMC3887521

See all PubMed Citations (5)

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004821866.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	29	not provided	not provided	clinical testing	PubMed (5)

Description

This missense variant replaces valine with isoleucine at codon 1014 of the DSG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been identified in three individuals affected with dilated cardiomyopathy (PMID: 20716751, 23861362, 24503780). This variant has been observed in a young individual with exertion-induced sudden unexplained death, who also carried a pathogenic variant in the MYBPC3 gene (PMID: 27114410). This variant has also been identified in 19/280798 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		29	not provided	not provided	not provided

Last Updated: May 16, 2025

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