ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.961G>C (p.Val321Leu) (rs143994626)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000426226 SCV000535064 uncertain significance not provided 2016-12-22 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DSP gene. The V321L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant was not observed with any significant frequency in the 1000 Genomes Project, the NHLBI Exome Sequencing Project, and the Exome Aggregation Consortium (ExAC), indicating it is not a common benign variant in these populations. However, V321L is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, although this substitution occurs at a position that is conserved in mammals, Leucine is the wild-type residue at this position in at least one mammalian and one non-mammalian species. Finally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000704787 SCV000833751 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-11-30 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 321 of the DSP protein (p.Val321Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. This variant is present in population databases (rs143994626, ExAC 0.03%). This variant has not been reported in the literature in individuals with DSP-related disease. ClinVar contains an entry for this variant (Variation ID: 391896). 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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