ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.2799G>C (p.Leu933Phe) (rs372922674)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255568 SCV000321566 uncertain significance not specified 2016-06-13 criteria provided, single submitter clinical testing The L933F variant of uncertain significance has been identified in the DSP gene. The L933F variant has not been published as a pathogenic variant or been reported as a benign variant to our knowledge. The L933F variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. This substitution occurs at a position that is conserved across species. However, the L933F variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Consequently, in silico analysis is inconsistent in its predictions as to whether or not this variant is damaging to the protein structure/function. In addition, no definitive pathogenic missense variants in nearby residues have been reported in the Human Gene Mutation Database (Stenson P et al., 2014).Therefore, based on the currently available information, it is unclear whether the L933F variant in the DSP gene is pathogenic or benign.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000255568 SCV000711382 uncertain significance not specified 2017-01-11 criteria provided, single submitter clinical testing The p.Leu933Phe variant in DSP has been reported in 1 individual with ARVC (Wals h 2016). This variant has also been reported in ClinVar (Variation ID 265104). T his variant has been identified in 8/65790 European chromosomes by the Exome Agg regation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs372922674). C omputational prediction tools and conservation analysis do not provide strong su pport for or against an impact to the protein. In summary, the clinical signific ance of the p.Leu933Phe variant is uncertain.
Ambry Genetics RCV000620068 SCV000737482 uncertain significance Cardiovascular phenotype 2016-03-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient or conflicting evidence
Invitae RCV000699886 SCV000828616 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-11-16 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 933 of the DSP protein (p.Leu933Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs372922674, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with arrythmogenic right ventricular cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 265104). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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.

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