ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.2684A>G (p.Tyr895Cys) (rs367752002)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000171390 SCV000233596 uncertain significance not provided 2018-10-17 criteria provided, single submitter clinical testing The Tyr895Cys variant in the DSP gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Tyr895Cys results in a semi-conservative amino acid substitution of a neutral, polar Tyrosine with a neutral, polar Cysteine that could affect disulfide bonding. This substitution occurs at a position that is conserved across species and consequently, in silico analysis predicts Tyr895Cys is damaging to the protein structure/function. In addition, the Tyr895Cys variant was not observed with any significant frequency in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. However, definitive missense mutations in nearby residues have not been reported (Van der Zwaag P et al., 2009), indicating this region of the protein may be tolerant of change. With the clinical and molecular information available at this time, we cannot definitively determine if Tyr895Cys is a disease-causing mutation or a rare benign variant.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000171390 SCV000603391 uncertain significance not provided 2017-05-17 criteria provided, single submitter clinical testing The p.Tyr895Cys variant (rs367752002) has not been reported in the medical literature nor has it been previously identified in our laboratory; however, it is listed in the ClinVar database as a variant of uncertain significance (Variation ID: 163257). It is listed in the Genome Aggregation Database (gnomAD) browser with an overall frequency of 0.0004% (identified in 41 out of 277,050 chromosomes). The tyrosine at codon 895 is moderately conserved considering 12 species (Alamut software v2.9), and computational analyses return mixed results regarding the effect of this variant on DSP protein structure/function (SIFT: tolerated, PolyPhen2: possibly damaging, and Mutation Taster: disease causing). Thus, based on the available information, the clinical significance of the p.Tyr895Cys variant cannot be determined with certainty.
Color RCV000777747 SCV000913709 uncertain significance Cardiomyopathy 2018-08-27 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the plakin domain of the DSP protein. 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 the 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 41/277050 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000150562 SCV000197806 uncertain significance not specified 2008-03-01 no assertion criteria provided clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Blueprint Genetics RCV000157192 SCV000206916 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2014-09-18 no assertion criteria provided clinical testing
Developmental Genetics Unit,King Faisal Specialist Hospital & Research Centre RCV000171390 SCV000221587 likely pathogenic not provided no assertion criteria provided research

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