ClinVar Miner

Submissions for variant NM_000384.3(APOB):c.8720G>A (p.Arg2907His) (rs751437976)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000583176 SCV000687271 uncertain significance Familial hypercholesterolemia 1 2017-10-02 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant is a missense variant located in the beta2 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 9/121330 chromosomes (7/16502 in South Asian chromosomes) by the Exome Aggregation Consortium (ExAC) general population database.
Color RCV000775483 SCV000909846 likely benign Familial hypercholesterolemia 2018-05-23 criteria provided, single submitter clinical testing Likely Benign based on current evidence: This missense variant (also known as p.Arg2880His in the mature protein) is 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. This variant occurs in more than 10 mammalian species, suggesting that the variant is functionally tolerated. 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 familial hypercholesterolemia in the literature. This variant has been identified in 14/246020 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Benign.
Invitae RCV000800078 SCV000939777 uncertain significance Familial hypercholesterolemia 2; Hypobetalipoproteinemia, familial, 1 2018-11-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 2907 of the APOB protein (p.Arg2907His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs751437976, ExAC 0.04%), 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: 490402). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine 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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