ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.4997G>A (p.Arg1666Gln) (rs768577891)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181261 SCV000233544 uncertain significance not provided 2017-05-18 criteria provided, single submitter clinical testing The R1666Q variant of uncertain significance in the DSP gene has not been published as pathogenic or been reported as benign to our knowledge. This variant was not observed at any significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R1666Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved across species, and where Glutamine (Q) is the wild-type allele in multiple species. Moreover, two of three in silico analysis algorithms predict this variant likely does not alter the protein structure/function. Nevertheless, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000641770 SCV000763418 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2017-11-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1666 of the DSP protein (p.Arg1666Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs768577891, ExAC 0.009%). This variant has not been reported in the literature in individuals with DSP-related disease. ClinVar contains an entry for this variant (Variation ID: 199841). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Color RCV000778028 SCV000914140 uncertain significance Cardiomyopathy 2018-07-29 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. Computational prediction tools and conservation analyses suggest that this variant may not impact 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 11/245922 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.

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