ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.6248G>A (p.Arg2083His) (rs574637009)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181339 SCV000233636 uncertain significance not provided 2013-06-12 criteria provided, single submitter clinical testing p.Arg2083His (CGT>CAT): c.6248 G>A in exon 24 of the DSP gene (NM_004415.2). The Arg2083His variant in the DSP gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Arg2083His results in a conservative amino acid substitution of one positively charged amino acid with another at a position that is conserved across species. In silico analysis predicts Arg2083His is damaging to the protein structure/function. The Arg2083His variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Nevertheless, no mutations in nearby residues have been reported in association with ARVC, 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 Arg2083His is a disease-causing mutation or a rare benign variant. The variant is found in ARVC panel(s).
Invitae RCV000463211 SCV000543276 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2016-05-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 2083 of the DSP protein (p.Arg2083His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs574637009, ExAC 0.01%) but has not been reported in the literature in individuals with a DSP-related disease. ClinVar contains an entry for this variant (Variation ID: 199900). 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 C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000181339 SCV000924783 uncertain significance not provided 2016-07-27 no assertion criteria provided provider interpretation p.Arg2083His (c.6248G>A) in DSP gene (NM_004415.2) Seen in a patient in our center with recurrent unexplained ventricular tachycardia and ventricular fibrillation as well as intellectual disability. Given the novel nature of this variant, we consider this missense variant to be a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The DSP gene has been reported in OMIM to be associated with the following phenotypes: arrhythmogenic right ventricular dysplasia 8, dilated cardiomyopathy with wooly hair and keratoderma, and dilated cardiomyopathy with woolly hair, keratoderma and tooth agenesis. Per our own searches and the lab report, it appears the variant has not been reported in individuals with heart problems. The variant has been seen in 1 of 60,300 individuals. It was reported in 1 individual in ExAC. Specifically, the variant has been observed in the following ethnicity: African, 1/5,069. The population frequency of this variant is 0.001%. The phenotype of this individual is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). Another variant in the same location, c.6248C>T (p.Arg2083Cys), has been reported in 5 individuals in ExAC. Specifically, the variant has been observed in the following ethnicities: African: 1/5,069, European (non-Finnish): 4/33,123.

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