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NM_001943.5(DSG2):c.3295A>G (p.Thr1099Ala) AND not specified

Germline classification:
Benign/Likely benign (2 submissions)
Last evaluated:
Sep 8, 2020
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:
RCV000037302.8

Allele description [Variation Report for NM_001943.5(DSG2):c.3295A>G (p.Thr1099Ala)]

NM_001943.5(DSG2):c.3295A>G (p.Thr1099Ala)

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.3295A>G (p.Thr1099Ala)
HGVS:
  • NC_000018.10:g.31546681A>G
  • NG_007072.3:g.53440A>G
  • NM_001943.5:c.3295A>GMANE SELECT
  • NP_001934.2:p.Thr1099Ala
  • LRG_397t1:c.3295A>G
  • LRG_397:g.53440A>G
  • NC_000018.9:g.29126644A>G
  • NM_001943.3:c.3295A>G
  • NM_001943.4:c.3295A>G
  • c.3295A>G
Protein change:
T1099A
Links:
dbSNP: rs79068489
NCBI 1000 Genomes Browser:
rs79068489
Molecular consequence:
  • NM_001943.5:c.3295A>G - missense variant - [Sequence Ontology: SO:0001583]
Observations:
2

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000060959Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(LMM Criteria)		Likely benign
(May 24, 2012) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001437286Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Benign
(Sep 8, 2020) 		germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot provided22not providednot providednot providedclinical 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

Distinguishing arrhythmogenic right ventricular cardiomyopathy/dysplasia-associated mutations from background genetic noise.

Kapplinger JD, Landstrom AP, Salisbury BA, Callis TE, Pollevick GD, Tester DJ, Cox MG, Bhuiyan Z, Bikker H, Wiesfeld AC, Hauer RN, van Tintelen JP, Jongbloed JD, Calkins H, Judge DP, Wilde AA, Ackerman MJ.

J Am Coll Cardiol. 2011 Jun 7;57(23):2317-27. doi: 10.1016/j.jacc.2010.12.036.

PubMed [citation]
PMID:
21636032
PMCID:
PMC6311127
See all PubMed Citations (4)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000060959.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testing PubMed (1)

Description

Thr1099Ala in exon 15 of DSG2: This variant is not expected to have clinical sig nificance because it has been identified in 0.5% (15/3328) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs79068489). Thr1099Ala in exon 15 of DSG2 (r s79068489; allele frequency = 0.5%, 15/3328) **

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided2not provided2not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001437286.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

Variant summary: DSG2 c.3295A>G (p.Thr1099Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00039 in 281622 control chromosomes, predominantly at a frequency of 0.0041 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 410 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSG2 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.3295A>G has been reported in the literature in one individual affected with DCM (Garcia-Pavia_2011). The data does not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as benign (1x) and likely benign (4x). Based on the evidence outlined above, the variant was classified as benign.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 12, 2024