ClinVar Miner

Submissions for variant NM_000384.3(APOB):c.10778C>T (p.Pro3593Leu) (rs1553382921)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000518953 SCV000621941 uncertain significance not provided 2017-11-02 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the APOB gene. The P3593L variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016). The P3593L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Although this substitution occurs at a position that is not conserved where leucine (L) is tolerated in several species, in silico analysis predicts this variant is probably damaging to the protein structure/function.
Invitae RCV001065717 SCV001230690 uncertain significance Familial hypercholesterolemia 2; Hypobetalipoproteinemia, familial, 1 2019-05-03 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 3593 of the APOB protein (p.Pro3593Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with APOB-related conditions. ClinVar contains an entry for this variant (Variation ID: 453083). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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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