ClinVar Miner

Submissions for variant NM_000384.3(APOB):c.8550T>G (p.Ile2850Met) (rs148498577)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000455427 SCV000538323 uncertain significance not specified 2016-03-28 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Only 1 paper (lower freq in cases than controls); ExAC: 13/66698 European
Invitae RCV000531740 SCV000659304 uncertain significance Hypercholesterolemia, autosomal dominant, type B; Hypobetalipoproteinemia, familial, 1 2018-04-18 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with methionine at codon 2850 of the APOB protein (p.Ile2850Met). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is present in population databases (rs148498577, ExAC 0.02%) and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in the literature in an individual with dyslipidemia (PMID: 24503134) and in one control individual (PMID: 22923420). ClinVar contains an entry for this variant (Variation ID: 402376). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 402376).
Robarts Research Institute,Western University RCV000660701 SCV000782886 uncertain significance Familial hypercholesterolemia 2018-01-02 criteria provided, single submitter clinical testing
Color RCV000771172 SCV000903103 uncertain significance Familial hypercholesterolemias 2018-05-15 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant (also known as p.Ile2823Met in the mature protein) is a missense variant located in the beta 2 domain of the APOB protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has been reported in an individual with suspected monogenic dyslipidemia (PMID: 24503134). This variant has also been identified in 41/276768 chromosomes (39/126470 non-Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.

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