ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.3616T>A (p.Leu1206Ile) (rs151115778)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000727240 SCV000233540 uncertain significance not provided 2017-10-31 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DSP gene. The L1206I variant has not been published as pathogenic or been reported as benign to our knowledge. The L1206I variant is not observed in large population cohorts (Lek et al., 2016). However, the L1206I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to leucine (L) are tolerated across species and where isolecuine (I) is present as the wild type in at least two species. Finally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000238924 SCV000297156 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2015-11-16 criteria provided, single submitter clinical testing
Invitae RCV000461417 SCV000543224 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-02-15 criteria provided, single submitter clinical testing This sequence change replaces leucine with isoleucine at codon 1206 of the DSP protein (p.Leu1206Ile). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and isoleucine. This variant is present in population databases (rs151115778, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with DSP-related disease. ClinVar contains an entry for this variant (Variation ID: 199839). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000727240 SCV000706883 uncertain significance not provided 2017-03-10 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780218 SCV000917307 likely benign not specified 2018-10-15 criteria provided, single submitter clinical testing Variant summary: DSP c.3616T>A (p.Leu1206Ile) results in a 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 9e-05 in 276874 control chromosomes, predominantly at a frequency of 0.00019 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 19 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.3616T>A has been reported in the literature in a DCM family segregating with a likely pathogenic (class IV) RBM20 variant, p.Ser635Cys that the authors believed to be the cause for disease (Klauke_2017). This DSP variant was classified as a VUS (class 3 variant) and was reportedly identified in all genetically tested family members in this study. We interpret this to mean that the variant was present in both affected (i.e., the RBM20 variant positive) and unaffected (i.e., the RBM20 negative) members of this DCM kindred. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Erich and Hanna Klessmann Institute for Cardiovascular Research and Development,Heart and Diabetes Center North Rhine-Westphalia RCV000491844 SCV000298123 uncertain significance Dilated cardiomyopathy 1S 2016-05-01 no assertion criteria provided clinical testing

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