ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.2683T>C (p.Tyr895His) (rs375891215)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766878 SCV000321565 uncertain significance not provided 2018-07-30 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DSP gene. The Y895H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It has been seen in one other individual referred for cardiomyopathy testing at GeneDx, however, this individual also harbored additional variants of uncertain significance. Y895H 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. Moreover, this substitution occurs at a position that is conserved in mammals. While the Y895H 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, it has been observed in 2/1322 alleles (0.15%) from individuals of African American ancestry in the 1000 Genomes Project. Finally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000463686 SCV000543256 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2017-03-02 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 895 of the DSP protein (p.Tyr895His). The tyrosine residue is moderately conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is present in population databases (rs375891215, ExAC 0.1%) but has not been reported in the literature in individuals with a DSP-related disease. ClinVar contains an entry for this variant (Variation ID: 265103). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000255188 SCV000710900 uncertain significance not specified 2017-12-15 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Tyr895His var iant in DSP has been reported in 1 individual with DCM (Haskell 2017). It has be en identified in 0.14% (34/24034) of African chromosomes by the Genome Aggregati on Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs375891215). This variant has also been reported in ClinVar (Variation ID:265103). Computational p rediction tools and conservation analysis do not provide strong support for or a gainst an impact to the protein. In summary, while the clinical significance of the p.Tyr895His variant is uncertain, its frequency suggests that it is more lik ely to be benign. ACMG/AMP Criteria applied: BS1.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678703 SCV000804867 uncertain significance Left ventricular hypertrophy 2015-11-04 no assertion criteria provided clinical testing
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678704 SCV000804868 uncertain significance Sudden death 2017-06-16 no assertion criteria provided clinical testing

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