ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.6397G>A (p.Gly2133Ser) (rs372393122)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766888 SCV000233637 uncertain significance not provided 2014-07-08 criteria provided, single submitter clinical testing p.Gly2133Ser (GGT>AGT): c.6397 G>A in exon 24 of the DSP gene (NM_004415.2). The G2133S variant has not been published as a mutation or as a benign polymorphism to our knowledge. The G2133S variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In addition, the G2133S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Furthermore, this substitution occurs at a position that is completely conserved across species. In silico analysis predicts this variant is possibly damaging to the protein structure/function. Nevertheless, no missense mutations in nearby residues have been reported in association with ARVC, indicating this region of the protein may be tolerant of change.Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s).
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000181340 SCV000271739 uncertain significance not specified 2015-12-10 criteria provided, single submitter clinical testing The p.Gly2133Ser variant in DSP has not been previously reported in individuals with cardiomyopathy, but has been identified in 4/8620 East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s372393122). Computational prediction tools and conservation analysis suggest th at the p.Gly2133Ser variant may impact the protein, though this information is n ot predictive enough to determine pathogenicity. In summary, the clinical signif icance of the p.Gly2133Ser variant is uncertain.
Integrated Genetics/Laboratory Corporation of America RCV000181340 SCV000919289 uncertain significance not specified 2018-01-25 criteria provided, single submitter clinical testing Variant summary: The DSP c.6397G>A (p.Gly2133Ser) variant involves the alteration of a conserved nucleotide located at the Plectin repeat domain of the protein (InterPro). 3/3 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index, Polyphen not accessible at the time of evaluation). This variant was found in 9/276996 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.000424 (8/18860). This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic DSP variant (0.0002), suggesting this is possibly a benign polymorphism found primarily in the populations of East Asian origin. Although the gnomAD dataset possibly includes cardio patients, thus this frequency needs to be taken with caution. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. One internal sample also carried a likely pathogenic variant in DSP, c.1825C>T/p.Gln609X, suggesting non-pathgoenic role of this variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a VUS-possibly benign until additional information becomes available.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678705 SCV000804869 uncertain significance Left ventricular noncompaction cardiomyopathy 2016-03-22 no assertion criteria provided clinical testing

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