ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.2546A>G (p.Tyr849Cys) (rs778636665)

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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 RCV000218085 SCV000271722 uncertain significance not specified 2015-08-24 criteria provided, single submitter clinical testing The p.Tyr849Cys variant in DSP has not been previously reported in individuals w ith cardiomyopathy, but has been identified in 12/66738 European chromosomes by the Exome Aggregation Consortium (ExAC,; dbSNP rs 778636665). Tyrosine (Tyr) at position 849 is not conserved in mammals or evolut ionarily distant species and 1 mammal (opossum) and several fish species carry a cysteine (Cys) at this position, raising the possibility that this change may b e tolerated. In summary, the clinical significance of the p.Tyr849Cys variant is uncertain.
Invitae RCV000468852 SCV000543231 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2017-11-07 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 849 of the DSP protein (p.Tyr849Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs778636665, 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. 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.
GeneDx RCV000766550 SCV000567658 uncertain significance not provided 2016-11-22 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DSP gene. The Y849C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The Y849C variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Y849C variant 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. Although this substitution occurs at a position that is conserved in mammals, C849 is wild type at this position in multiple non-mammalian species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Ambry Genetics RCV000620836 SCV000737780 uncertain significance Cardiovascular phenotype 2016-11-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence

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