ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.6269A>G (p.Glu2090Gly) (rs755069593)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000641824 SCV000763474 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2017-11-02 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glycine at codon 2090 of the DSP protein (p.Glu2090Gly). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is present in population databases (rs755069593, ExAC 0.003%). This variant has not been reported in the literature in individuals with DSP-related disease. ClinVar contains an entry for this variant (Variation ID: 234989). 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 disruptive, 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.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223906 SCV000280094 uncertain significance not specified 2014-05-16 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Given the lack of case data and the type of variant, we consider this variant a variant of uncertain significance. We could find no reported cases of disease with this variant. Specifically, it is not listed in ClinVar or the ARVD mutation database. PolyPhen2 and MutationTaster both predict the variant to be disease causing with scores of 0.985 and 1.000 respectively. SIFT does not predict the variant to be disease causing, though the score (0.93) is close to the cutoff (0.95). The glutamic acid at codon 2090 is completely conserved across species. It is notable that most pathogenic variants in DSP are not missense. The variant was reported online in 2 of 60431 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of September 22nd, 2015). Specifically, the variant was observed in 2 of 33217 European individuals. The phenotype of those individuals 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).

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