ClinVar Miner

Submissions for variant NM_017890.4(VPS13B):c.10624A>G (p.Lys3542Glu) (rs143187571)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory,University of Chicago RCV000192802 SCV000249394 uncertain significance not specified 2014-10-09 criteria provided, single submitter clinical testing
GeneDx RCV000766563 SCV000577343 uncertain significance not provided 2017-04-03 criteria provided, single submitter clinical testing The K3542E variant in the VPS13B gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is observed in 12/66738 (0.02%) alleles from individuals of non-Finnish European background in the ExAC dataset (Lek et al., 2016). This substitution occurs at a position where amino acids with similar properties to Lysine are tolerated across species. However, the K3542E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret K3542E as a variant of uncertain significance.
Invitae RCV001055358 SCV001219746 uncertain significance Cohen syndrome 2019-09-16 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 3542 of the VPS13B protein (p.Lys3542Glu). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is present in population databases (rs143187571, ExAC 0.02%). This variant has not been reported in the literature in individuals with VPS13B-related conditions. ClinVar contains an entry for this variant (Variation ID: 212568). 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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