NM_001943.5(DSG2):c.3040G>A (p.Val1014Ile) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Apr 10, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000037296.8

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)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000060953	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Jul 30, 2012)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 20716751, 24033266
SCV000697887	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Apr 10, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 20716751, 23861362, 24503780, 27114410, 27532257, 28600387 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000060953

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Jul 30, 2012)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV000697887

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Apr 10, 2022)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	1	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

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

See all PubMed Citations (7)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000060953.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (2)

Description

The Val1014Ile variant in DSG2 has been reported in 1 individual with DCM and wa s absent from 400 control chromosomes (Elliott 2010). In addition, this variant has been identified in 3/8352 European American chromosomes from a broad populat ion by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). C omputational analyses (biochemical amino acid properties, conservation, AlignGVG D, PolyPhen2, and SIFT) do not provide strong support for or against an impact t o the protein. Additional information is needed to fully assess the clinical sig nificance of the Val1014Ile variant.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697887.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Variant summary: DSG2 c.3040G>A (p.Val1014Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 249792 control chromosomes. The observed variant frequency is approximately 7.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSG2 (1e-05), strongly suggesting that the variant is benign. c.3040G>A has been reported in the literature as a VUS in settings of multigene panel testing of individuals with a variety of cardiac phenotypes such as idiopathic dilated cardiomyopathy (DCM), DCM, exertion-related sudden unexplained death in the young (SUDY) (example, Elliott_2010, Pugh_2014, Anderson_2016, Mellor_2017, Walsh_2017) and as a Likely Pathogenic cardiomyopathy associated variant in at-least one individual with hypertension/stroke (example, Ng_2013). These data do not allow any conclusion about variant significance. At-least one of these reports mentions a co-occurrence with another pathogenic variant in an individual with exertion-related sudden unexplained death in the young (SUDY) (MYBPC3 c.2374T>C, p.Trp792Arg), providing supporting evidence for a benign role (Anderson_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=5; Likely benign, n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

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

Last Updated: May 16, 2025

ClinVar

Relating variation to medicine