ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.1788G>A (p.Ala596=) (rs146161960)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000554581 SCV000408099 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 11 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV000554581 SCV000644996 likely benign Arrhythmogenic right ventricular cardiomyopathy, type 11 2019-12-31 criteria provided, single submitter clinical testing
GeneDx RCV000606828 SCV000723443 likely benign not specified 2017-01-18 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.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001171302 SCV001334026 benign Cardiomyopathy 2017-12-01 criteria provided, single submitter clinical testing
Color RCV001171302 SCV001347323 likely benign Cardiomyopathy 2018-12-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000606828 SCV001361048 benign not specified 2019-01-28 criteria provided, single submitter clinical testing Variant summary: DSC2 c.1788G>A alters a non-conserved nucleotide resulting in a synonymous change. 4/5 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 0.00012 in 276856 control chromosomes (gnomAD). The observed variant frequency is approximately 5 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 benign. To our knowledge, no occurrence of c.1788G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submissions from clinical diagnostic laboratories and reputable databases (evaluation after 2014) cite the variant as likely benign (2x) and once as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000606828 SCV001365490 likely benign not specified 2012-03-19 criteria provided, single submitter clinical testing p.Ala596Ala in Exon 12 of DSC2: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located within the splice consensus sequence. It has been identified in 1/7020 European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs146161960).

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