ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.3956C>G (p.Thr1319Ser) (rs138599871)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000156223 SCV000205939 uncertain significance not specified 2013-11-20 criteria provided, single submitter clinical testing The Thr1319Ser variant in DSP has not been previously reported in individuals wi th cardiomyopathy and was absent from large population studies. Computational an alyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, a nd SIFT) do not provide strong support for or against an impact to the protein. In summary, additional information is needed to fully assess the clinical signif icance of this variant.
GeneDx RCV000766823 SCV000590666 uncertain significance not provided 2017-06-19 criteria provided, single submitter clinical testing The T1319S variant has not been published as pathogenic or been reported as benign to our knowledge. This substitution occurs at a position that is conserved in mammals. Nevertheless, The T1319S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Finally, the Exome Aggregation Consortium reports T1319S was observed in 6/16468 (0.04%) alleles from individuals of South Asian background (Lek et al., 2016).
Color RCV000778002 SCV000914110 uncertain significance Cardiomyopathy 2018-10-29 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the central rod domain of the DSP protein that is thought to form a dimeric coiled coil. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 19/245574 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Integrated Genetics/Laboratory Corporation of America RCV000156223 SCV000919287 likely benign not specified 2018-03-26 criteria provided, single submitter clinical testing Variant summary: DSP c.3956C>G (p.Thr1319Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 49 fold above 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 South Asian origin. To our knowledge, no occurrence of c.3956C>G in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.

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