ClinVar Miner

Submissions for variant NM_000384.3(APOB):c.4532C>T (p.Thr1511Ile) (rs146247063)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523023 SCV000619304 uncertain significance not provided 2017-07-19 criteria provided, single submitter clinical testing The T1511I variant in the APOB gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The T1511I variant is observed in 3/6612 (0.045%) alleles from individuals of Finnish European background in the ExAC dataset (Lek et al., 2016). The T1511I 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 that is not conserved across species, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret T1511I as a variant of uncertain significance.
Robarts Research Institute,Western University RCV000660688 SCV000782856 uncertain significance Familial hypercholesterolemia 1 2018-01-02 criteria provided, single submitter clinical testing
Color RCV000771242 SCV000903342 uncertain significance Familial hypercholesterolemia 2018-11-16 criteria provided, single submitter clinical testing
Invitae RCV001245523 SCV001418816 uncertain significance Familial hypercholesterolemia 2; Hypobetalipoproteinemia, familial, 1 2019-09-16 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 1511 of the APOB protein (p.Thr1511Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs146247063, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with APOB-related disease. ClinVar contains an entry for this variant (Variation ID: 450695). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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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