ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.3295A>G (p.Thr1099Ala) (rs79068489)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037302 SCV000060959 likely benign not specified 2012-05-24 criteria provided, single submitter clinical testing 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) **
Illumina Clinical Services Laboratory,Illumina RCV001082544 SCV000408270 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.
GeneDx RCV000037302 SCV000512870 likely benign not specified 2017-10-02 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV001082544 SCV000561382 benign Arrhythmogenic right ventricular cardiomyopathy, type 10 2020-12-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000622126 SCV000734907 likely benign Cardiovascular phenotype 2018-09-27 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Color Health, Inc RCV000771829 SCV000904542 likely benign Cardiomyopathy 2018-10-20 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000845296 SCV000987328 likely benign not provided criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000037302 SCV001437286 benign not specified 2020-09-08 criteria provided, single submitter clinical testing 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.

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