ClinVar Miner

Submissions for variant NM_000384.3(APOB):c.13181T>C (p.Val4394Ala) (rs12720843)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000455704 SCV000538335 uncertain significance not specified 2017-03-01 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: 2 papers from HGMD. Fochier 2005 (16250003) detected variant in 1 individual with FH but no additional information. Huijgen 2010 (20506408) found that this variant doesn't segregate with hypercholesterolemia (LDL levels) in 6 families vs non-carriers. Low freq in ExAC.
Invitae RCV000531054 SCV000659267 uncertain significance Familial hypercholesterolemia 2; Hypobetalipoproteinemia, familial, 1 2017-12-12 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 4394 of the APOB protein (p.Val4394Ala). The valine residue is moderately conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs12720843, ExAC 0.03%). This variant has been reported in the literature in individuals affected with hypercholesterolemia (PMID: 16250003, 20506408). However in one family this variant did not segregate with disease and was called likely non-pathogenic (PMID: 20506408). This variant is also known in the literature as p.Val4367Ala. 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: "Benign"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change that showed lack of segregation with disease and it has an uncertain impact on protein function. It is not expected to cause disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV000775427 SCV000909790 uncertain significance Familial hypercholesterolemia 2018-07-29 criteria provided, single submitter clinical testing Variant of Uncertain Significance based on current evidence: This missense variant (also known as p.Val4367Ala in the mature protein) is located in the alpha 3 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. Segregation analysis of four families in the Netherlands indicated that this variant did not segregate with an autosomal dominant hypercholesterolemia phenotype (PMID: 20506408). This variant has been identified in 58/276364 chromosomes (51/125990 Non-Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Although there is no indication that this variant causes familial hypercholesterolemia, available evidence is insufficient to rule out the pathogenicity of this variant conclusively.

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