ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.3209C>T (p.Thr1070Met) (rs149617776)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000172531 SCV000054852 likely benign not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000154705 SCV000204384 likely benign not specified 2014-06-30 criteria provided, single submitter clinical testing Thr1070Met in exon 15 of DSG2: This variant is not expected to have clinical sig nificance because it is not conserved across species, including mammals. Of note , >15 mammals have a methionine (Met) at this position. In addition, computation al prediction tools do not suggest a high likelihood of impact to the protein. I t has also been identified in 5/8274 of European American chromosomes and by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs1496 17776).
Invitae RCV001079476 SCV000287241 benign Arrhythmogenic right ventricular cardiomyopathy, type 10 2020-12-04 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001079476 SCV000408265 likely benign Arrhythmogenic right ventricular cardiomyopathy, type 10 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000172531 SCV000609787 likely benign not provided 2017-03-08 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000154705 SCV000703280 benign not specified 2016-11-30 criteria provided, single submitter clinical testing
Ambry Genetics RCV000621371 SCV000737580 benign Cardiovascular phenotype 2016-10-20 criteria provided, single submitter clinical testing General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Color Health, Inc RCV000771264 SCV000903382 benign Cardiomyopathy 2018-05-11 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000172531 SCV000987418 benign not provided criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000771264 SCV001332957 benign Cardiomyopathy 2018-07-19 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000154705 SCV001362563 benign not specified 2019-01-21 criteria provided, single submitter clinical testing Variant summary: DSG2 c.3209C>T (p.Thr1070Met) 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 0.0017 in 277006 control chromosomes, predominantly at a frequency of 0.0087 within the Latino subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 348 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSG2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.3209C>T has been reported in the literature among 870 participants not selected for arrhythmia, cardiomyopathy (Ng_2013). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant predomiantly as likely benign/benign (4x) and once as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000172531 SCV001741493 likely benign not provided no assertion criteria provided clinical testing

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