ClinVar Miner

Submissions for variant NM_000384.3(APOB):c.5066G>A (p.Arg1689His) (rs151009667)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute for Integrative and Experimental Genomics,University of Luebeck RCV000172971 SCV000212149 likely benign Familial hypercholesterolemia criteria provided, single submitter research
Robarts Research Institute,Western University RCV000172971 SCV000484823 uncertain significance Familial hypercholesterolemia criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000455619 SCV000538326 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: Nonsegs reported, ExAC: 0.2% (146/66706) European chromosomes
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000172971 SCV000588437 uncertain significance Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
GeneDx RCV000455619 SCV000617638 uncertain significance not specified 2017-08-08 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the APOB gene. The R1689H variant has been reported in association with hypertriglyceridemia and hypercholesterolemia (Johansen et al., 2010; Radovica-Spalvina et al., 2015; Brænne et al., 2016). Johansen et al. (2010) identified R1689H (using alternate nomenclature of R1662H) in two patients from a hypertriglyceridemia cohort, although specific clinical details and family history information were not provided. Radovica-Spalvina et al. (2015) reported the R1689H variant in a Latvian patient with elevated LDL-C levels and coronary artery disease, as well as in an individual with elevated LDL-C levels from a population-based cohort. Subsequently, R1689H was reported in three German index patients with history of myocardial infarction (MI) prior to age 60; family member testing showed that on average, variant carriers had higher LDL-C levels than non-carriers, however, four variant carriers did not show elevated cholesterol levels and two non-carriers had LDLC levels greater than 190mg/dl (Brænne et al., 2016). Thus, study authors did not expect R1689H to be the cause of disease in these families or generally increase the risk of FH/MI (Brænne et al., 2016).The R1689H substitution occurs at a position that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, R1689H is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In addition, no pathogenic missense variants in nearby residues have been reported in the Human Gene Mutation Database (Stenson et al., 2014), indicating that this region of the gene is not known to harbor disease-causing variants. Finally, the R1689H variant was observed in 146/66,706 (0.22%) of alleles from individuals of European (Non-Finnish) ancestry in the Exome Aggregation Consortium (Lek et al., 2016).
Invitae RCV000558095 SCV000659286 likely benign Hypercholesterolemia, autosomal dominant, type B; Hypobetalipoproteinemia, familial, 1 2017-11-30 criteria provided, single submitter clinical testing
Color RCV000172971 SCV000687247 uncertain significance Familial hypercholesterolemia 2017-07-24 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant is a missense variant 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. In a study of individuals affected with myocardial infarction, this variant showed no correlation with cholesterol levels (PMID 26036859). This variant has been identified in 146/66706 non-Finnish European chromosomes by the Exome Aggregation Consortium (ExAC) general population database.
Color RCV000771127 SCV000902878 likely benign Familial hypercholesterolemias 2018-05-02 criteria provided, single submitter clinical testing Likely Benign variant based on current evidence: This missense variant (also known as p.Arg1662His in the mature protein) is located in the beta 1 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 this variant has not been investigated for functional impact in experimental studies nor has the variant been reported in individuals affected with familial hypercholesterolemia in the literature. In a study of individuals affected with myocardial infarction, carrier status of this variant showed no correlation with cholesterol levels (PMID: 26036859). This variant has been identified in 342/126440 non-Finnish European chromosomes (0.27%) in the general population by the Genome Aggregation Database (gnomAD). This variant allele frequency is greater than expected for the disorder based on prevalence, penetrance, and genetic/allelic heterogeneity. Based on available evidence, this variant is classified as Likely Benign.

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