ClinVar Miner

Submissions for variant NM_000384.3(APOB):c.8134C>T (p.Arg2712Cys) (rs372245645)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000776519 SCV000912115 uncertain significance Familial hypercholesterolemias 2018-09-11 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant (also known as p.Arg2685Cys in the mature protein) is a missense variant located in the beta 2 domain of the APOB protein. Computational prediction tools and conservation analyses suggest that this variant may not impact 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 the variant been reported in individuals affected with FH in the literature. This variant has been identified in 7/10146 Ashkenazi Jewish chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Invitae RCV000796713 SCV000936237 uncertain significance Hypercholesterolemia, autosomal dominant, type B; Hypobetalipoproteinemia, familial, 1 2018-11-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 2712 of the APOB protein (p.Arg2712Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs372245645, ExAC 0.02%), 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. 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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