ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.70-11del (rs572309510)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000150530 SCV000197738 likely benign not specified 2013-10-10 criteria provided, single submitter clinical testing 70-11delT in intron 1 of DSC2: This variant is not expected to have clinical sig nificance because it is located outside the conserved +/- 1, 2 region of the spl icing consensus sequence and as part of a polyT stretch. It does not alter the r egion of interest (ROI).
GeneDx RCV000150530 SCV000565787 benign not specified 2015-05-07 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.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000625012 SCV000743502 benign Arrhythmogenic right ventricular cardiomyopathy, type 11 2016-03-03 criteria provided, single submitter clinical testing
Color RCV001185996 SCV001352321 benign Cardiomyopathy 2018-11-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000150530 SCV001361049 benign not specified 2019-11-05 criteria provided, single submitter clinical testing Variant summary: DSC2 c.70-11delT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00034 in 238322 control chromosomes, predominantly at a frequency of 0.0024 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 96 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSC2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.70-11delT in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.

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