ClinVar Miner

Submissions for variant NM_014000.2(VCL):c.2365G>A (p.Glu789Lys) (rs745419923)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000465443 SCV000548798 uncertain significance Dilated cardiomyopathy 1W 2016-04-16 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 789 of the VCL protein (p.Glu789Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs745419923, ExAC 0.002%) but has not been reported in the literature in individuals with a VCL-related disease. 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. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000498277 SCV000590692 uncertain significance not provided 2017-06-21 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the VCL gene. The E789K variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E789K 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. However, this substitution occurs at a position where amino acids with similar properties to glutamic acid are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.

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