ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.7915C>T (p.Arg2639Trp) (rs771553674)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000461737 SCV000543236 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-10-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 2639 of the DSP protein (p.Arg2639Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs771553674, ExAC 0.01%). This variant has been reported in the literature in an individual affected with arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 20400443). 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. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786122 SCV000924784 uncertain significance not provided 2017-02-06 no assertion criteria provided provider interpretation Testing was performed by Invitae. Given the lack of case data and presence in population databases, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least 1 unrelated cases of ARVC (not including this patient's family). There have been no reports of this variant in cases of LVNC or left ventricular systolic dysfunction. The case data is weak. Fressart et al. (2010) report this variant in one of their index patients with ARVC. Patients were recruited in France and Switzerland. They classify it as a variant of uncertain significance but note that it had previously been reported as a mutation in Yu et al. (2008). However, it isn't completely clear that these are referring to the same variant. Yu et al. reports the DSP variant as c.7516G>A (p.Arg2339Gln) in one individual who did not meet criteria for ARVC, but who did have sustained VT, dilation of the RV and non-specific dysfunction of the RV. The transcript used in this paper is reported as the same transcript listed above. This is not the same c. or p. nomenclature. It seems likely that these are not, in fact, the same variant. In silico prediction models to not agree on the effect of this variant. There variant has been seen in 11 of 141,023 individuals listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The variant was specifically in 9 of 63,156 European individuals (MAF=0.007%) and 2 of 15,444 South Asian individuals (MAF=0.006%). Phenotypic information on these individuals is not publicly available.

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