ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.5912T>C (p.Leu1971Pro) (rs397516950)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000038070 SCV000061736 uncertain significance not specified 2012-04-10 criteria provided, single submitter clinical testing The Leu1971Pro variant (DSP) has not been reported in the literature nor previou sly identified by our laboratory. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that this var iant may impact the protein, though this information is not predictive enough to determine pathogenicity. Additional information is needed to fully assess the c linical significance of the Leu1971Pro variant.
Invitae RCV000688727 SCV000816350 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-03-28 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 1971 of the DSP protein (p.Leu1971Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is present in population databases (rs397516950, ExAC 0.01%). This variant has not been reported in the literature in individuals with DSP-related disease. ClinVar contains an entry for this variant (Variation ID: 44934). 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.
Integrated Genetics/Laboratory Corporation of America RCV000038070 SCV000919291 uncertain significance not specified 2017-10-23 criteria provided, single submitter clinical testing Variant summary: The DSP c.5912T>C (p.Leu1971Pro) variant involves the alteration of a conserved nucleotide and 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). However, these predictions have yet to be functionally assessed. This variant was found in 4/277060 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.000167 (4/23994). This frequency is about 7 times the estimated maximal expected allele frequency of a pathogenic DSP variant (0.000025), suggesting this is likely a benign polymorphism found primarily in the populations of African origin, although the allele count is small. An internal LCA sample also carried a pathogenic variant in TTR c.424G>A/p.Val142Ile, further supporting the non-pathogenic role of the variant of interest. In addition, one other clinical diagnostic laboratory classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a "Variant of Uncertain Significance (VUS) - Possibly Benign," until additional information becomes available.

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