ClinVar Miner

Submissions for variant NM_000384.3(APOB):c.5989G>A (p.Asp1997Asn)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000693755 SCV000821636 uncertain significance Hypercholesterolemia, autosomal dominant, type B; Hypobetalipoproteinemia, familial, 1 2018-03-26 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 1997 of the APOB protein (p.Asp1997Asn). The aspartic acid residue is weakly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs142661577, ExAC 0.05%). 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 output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine 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.
Color RCV000775508 SCV000909872 uncertain significance Familial hypercholesterolemias 2018-09-18 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant (also known as p.Asp1970Asn in the mature protein) is located in the beta 1 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 the variant been reported in individuals affected with familial hypercholesterolemia in the literature. This variant is has been identified in 21/24032 African 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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