ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.5101A>G (p.Ile1701Val) (rs794728154)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181383 SCV000233685 uncertain significance not provided 2014-09-22 criteria provided, single submitter clinical testing p.Ile1701Val (ATA>GTA): c.5101 A>G in exon 23 of the DSP gene (NM_004415.2). The I1701V variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The I1701V 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. The I1701V substitution occurs at a position that is class conserved among mammals. However, the I1701V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Additionally, missense mutations in nearby residues have not been reported, indicating this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s).
Invitae RCV000694585 SCV000823036 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-01-09 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 1701 of the DSP protein (p.Ile1701Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with DSP-related disease. ClinVar contains an entry for this variant (Variation ID: 199936). 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.

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