ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.5555G>A (p.Arg1852His) (rs193922669)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000618287 SCV000736004 uncertain significance Cardiovascular phenotype 2017-08-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000777717 SCV000913661 likely benign Cardiomyopathy 2018-10-29 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000623709 SCV000052333 likely benign not specified 2019-02-13 criteria provided, single submitter clinical testing Variant summary: DSP c.5555G>A (p.Arg1852His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 277212 control chromosomes, predominantly at a frequency of 0.0014 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.0002), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.5555G>A has been reported in the literature in a study that attempted to estimate the cardiovascular genetic risk in the Pakistani population in comparison with other continental populations using the 1000 genomes and the ExAC datasets. As this constitues the South Asian population referred above, this report does not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. Furthermore, the Atlas of Cardiac Genetic Variation cites this variant as unlikely to be pathogenic based on its ExAC population frequency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One of these labs classified the variant as likely benign while the other two classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Invitae RCV000641842 SCV000763492 likely benign Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2017-11-28 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000623709 SCV000740336 uncertain significance not specified 2017-03-31 criteria provided, single submitter clinical testing

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