ClinVar Miner

Submissions for variant NM_000384.3(APOB):c.10580G>A (p.Arg3527Gln) (rs5742904)

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Total submissions: 24
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000254882 SCV000612386 pathogenic not provided 2016-04-18 criteria provided, single submitter clinical testing
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000019479 SCV000322853 pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research 0/190 non-FH alleles
Color RCV000771116 SCV000902821 pathogenic Familial hypercholesterolemias 2018-01-22 criteria provided, single submitter clinical testing Pathogenic variant based on current evidence: This variant (also known as p.Arg3500Gln) is a missense variant in the beta 2 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. Experimental studies have shown that the variant may affect APOB protein conformation and impairs its binding to the LDLR protein (PMID: 8254047, 9486979, 10388479, 11115503, 15797858). This variant has been reported in numerous individuals with familial hypercholesterolemia in multiple populations (PMID: 1466657, 2563166, 8254047, 9104431, 9105560, 9603795, 10388479, 11137107, 11494965, 11781700, 18222178, 18325181, 1977310, 21059979, 21868016, 23375686, 24956927) and has been shown to segregate with hypercholesterolemia in multiple families (PMID: 2563166, 8254047, 21868016). A different missense variant at the same position (p.Arg3527Trp) has been found associated with hypercholesterolemia . This variant has been identified in 79/276468 chromosomes in the general population by the Genome Aggregation Database (gnomAD). APOB mutations show incomplete penetrance, so individuals with APOB mutations may show a less severe phenotype than familial hypercholesterolemia patients with LDLR mutations (PMID: 8141833, 21868016, 21513517; GeneReviews NBK174884). In summary, the mutant APOB protein harboring this variant is functionally defective and has shown significant clinical association with familial hypercholesterolemia. Based on available evidence, this variant is classified as Pathogenic.
Fundacion Hipercolesterolemia Familiar RCV000019479 SCV000607384 pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
GeneDx RCV000254882 SCV000322134 pathogenic not provided 2018-12-07 criteria provided, single submitter clinical testing The R3527Q pathogenic variant in the APOB gene, also denoted as R3500Q due to the use of alternate nomenclature, has been previously reported in association with apolipoprotein B deficiency and hypercholesterolemia (Soria et al., 1989; Tybjaerg-Hansen et al.,1998; Fisher et al., 1999; Bertolini et al., 2013; Norsworthy et al., 2014; Radovica-Splavina et al., 2015; Braenne et al., 2016). This variant has been shown to segregate with disease in multiple affected relatives from multiple families (Soria et al., 1989; Loux et al., 1993; Chatzistefanidis et al., 2013). Additionally, R3527Q has been reported as a founder mutation in the Old Order Amish population (Shen et al., 2010). This variant is observed in 73/126,056 alleles from individuals of Non-Finnish European ancestry in large population cohorts (Lek et al., 2016). The R3527Q variant is a semi-conservative amino acid substitution, which occurs at a position that is conserved across mammalian species. Moreover, functional studies indicate that the R3527Q variant causes decreased binding of the APOB protein to the LDL receptor (Fisher et al., 1999). Furthermore, a pathogenic missense variant at the same residue (R3527W, also denoted as R3500W due to the use of alternate nomenclature) has also been reported in association with FH (Gaffney et al., 1995; Fisher et al., 1999). Finally, R3527Q is classified as a pathogenic/likely pathogenic variant in ClinVar by at least two other clinical laboratories (SCV000271309.1, SCV000484820.1; Landrum et al., 2016).
GeneReviews RCV000412515 SCV000490148 pathogenic Hypercholesterolemia, autosomal dominant, type B 2016-12-08 no assertion criteria provided literature only
Genetic Services Laboratory, University of Chicago RCV000499833 SCV000593263 likely pathogenic Hypobetalipoproteinemia 2015-11-30 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000851289 SCV000778605 pathogenic Hypobetalipoproteinemia, familial, 1 2019-06-24 criteria provided, single submitter research
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000412515 SCV000891787 pathogenic Hypercholesterolemia, autosomal dominant, type B 2018-03-28 criteria provided, single submitter research
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000412515 SCV000839879 pathogenic Hypercholesterolemia, autosomal dominant, type B 2017-05-25 criteria provided, single submitter clinical testing This c.10580G>A (p.Arg3527Gln) variant in the APOB gene has previously been reported in multiple patients with hypercholesterolemia [PMID 2563166, 23375686, 18325181, 27497240, 24956927, 21059979, 9603795 among others, reported as p.Arg3500Gln]. This variant is the most common cause of hypercholesterolemia due to an APOB variant and is common among Northern European populations. This change disrupts the binding of low density lipoproteins (LDL) onto the LDL receptor. The receptor mediated catabolism is thus disrupted and LDL accumulates in the plasma. The disorder caused by this specific variant is sometimes referred as hypercholesterolemia, due to ligand-defective apo B [MIM 144010]. This variant has been observed in 28 heterozygous individuals from the ExAC database ( Arginine at position 3527 of the APOB protein is highly conserved within mammals. While not validated for clinical use, the computer-based algorithms predict this p.Arg3527Gln change to be deleterious. It is thus interpreted as a pathogenic variant.
Iberoamerican FH Network RCV000019479 SCV000748075 pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Illumina Clinical Services Laboratory,Illumina RCV000284412 SCV000426985 uncertain significance Familial hypobetalipoproteinemia 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000019479 SCV000426986 pathogenic Familial hypercholesterolemia 2016-06-14 criteria provided, single submitter clinical testing The c.10580G>A (p.Arg3527Gln) variant, also reported as p.Arg3500Gln, is well described in the literature and reported as one of the two most common variants associated with familial hypercholesterolemia, particularly in individuals of European ancestry (Youngblom et al. 2014). Across a selection of the available literature, the p.Arg3527Gln variant has been found in a heterozygous state in 42 patients (Tybjaerg-Hansen et al. 1998; Soria et al. 1989; Saint-Jore et al. 2000; Bednarska-Makaruk et al. 2001; Horvath et al. 2001; Braenne et al. 2016). Four of the studies demonstrated segregation of the variant with disease (Soria et al. 1989; Horvath et al. 2001; Saint-Jore et al. 2000; Braenne et al. 2016). Control data are unavailable for this variant which is reported at a frequency of 0.00081 in the European American population of the Exome Sequencing Project. Functional studies in transgenic mice showed that the variant resulted in defective LDL receptor binding (Boren et al. 2001). Based on the collective evidence, the p.Arg3527Gln variant is classified as pathogenic for familial hypercholesterolemia.
Institute for Integrative and Experimental Genomics,University of Luebeck RCV000019479 SCV000212143 likely pathogenic Familial hypercholesterolemia criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV000771116 SCV000918478 pathogenic Familial hypercholesterolemias 2017-11-10 criteria provided, single submitter clinical testing Variant summary: The APOB c.10580G>A (p.Arg3527Gln) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 79/279708 control chromosomes at a frequency of 0.0002824, which is approximately 9 times the estimated maximal expected allele frequency of a pathogenic APOB variant (0.0000313). However, this is a well-characterized pathogenic mutation and is known to be frequent in certain populations. The variant has been identified in many affected individuals and families with hypercholesterolemia and is common in central Europe, particularly in Switzerland (frequency, 1:209) and Belgium (frequency, 1:250) (Sabbagh_APOB_MolBiolRep_2007). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000627797 SCV000541940 pathogenic Hypercholesterolemia, autosomal dominant, type B; Hypobetalipoproteinemia, familial, 1 2019-01-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 3527 of the APOB protein (p.Arg3527Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs5742904, ExAC 0.04%). This variant is a very well known cause of hypercholesterolemia due to APOB deficiency mainly in people of European ancestry (PMID: 24404629). It has been reported to segregate in families affected with hypercholesterolemia (PMID: 2563166, 21868016) and has been reported in multiple affected unrelated individuals (PMID: 9105560, 21059979, 18325181, 18222178, 10388479, 23375686). This variant is also known in the literature as p.Arg3500Gln. ClinVar contains an entry for this variant (Variation ID: 17890). Experimental studies have shown that this missense change disturbs the APOB protein conformation preventing it from binding LDL, therefore disturbing its normal function as inhibitor of the LDL receptor (PMID: 11115503, 15797858). A different missense substitution at this codon (p.Arg3527Trp) is reported to be deleterious (PMID: 7627691). This indicates that the arginine residue is important for APOB protein function. For these reasons, this variant has been classified as Pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000019479 SCV000605966 pathogenic Familial hypercholesterolemia no assertion criteria provided research
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000844612 SCV000271309 pathogenic Familial hypercholesterolemia - homozygous 2015-11-11 criteria provided, single submitter clinical testing The p.Arg3527Gln variant in APOB is a well-established pathogenic variant that i s mainly found in individuals of European descent. It has been previously report ed in >500 individuals with familial hypercholesterolemia (FH) and segregated wi th disease in >50 affected relatives (Soria 1989, Marz 1993, Leren 1997, Ludwig 1990, Bednarska-Makaruk 2001, Horvath 2001, Kalina 2001). It has also been repor ted by other clinical laboratories in ClinVar (Variation ID 17890) and has been identified in 53/126056 of European chromosomes, including 1 homozygote, by gnom AD ( This frequency is low enough to be consi stent with the frequency of FH in the general population. In summary, this varia nt meets criteria to be classified as pathogenic for autosomal dominant familial hypercholesterolemia based upon presence in multiple affected individuals and s egregation studies. Please note that pathogenic variants in APOB can have reduce d penetrance and a less severe phenotype than disease-causing LDLR or PCSK9 vari ants (Youngblom and Knowles, GeneReviews). ACMG/AMP Criteria applied: PS4_Strong ; PP1_Strong.
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000019479 SCV000588451 pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000412515 SCV000987576 pathogenic Hypercholesterolemia, autosomal dominant, type B criteria provided, single submitter clinical testing
OMIM RCV000412515 SCV000039775 pathogenic Hypercholesterolemia, autosomal dominant, type B 2001-11-01 no assertion criteria provided literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000254882 SCV000887561 pathogenic not provided 2018-07-11 criteria provided, single submitter clinical testing
Robarts Research Institute,Western University RCV000019479 SCV000484820 pathogenic Familial hypercholesterolemia 2019-08-22 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000254882 SCV000924752 pathogenic not provided 2017-05-16 no assertion criteria provided provider interpretation p.Arg3527Gln (c.10580G>A) in the APOB gene (NM_000384.2) Given the overwhelming case data and that this is a founder variant, we consider this variant pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant is frequently reported in the literature as p.Arg3500Gln. Per the test report, this variant has been reported to be responsible for 2-6% of Western European FH cases and has been reported as an Amish founder mutation (Heath KE et al. Atherosclerosis. 1999;143(1):41-54; Lombardi et al. Clin Genet. 2000;57(2):116-24; Chmara M et al. J Appl Genet. 2010;51(1):95-106; Shen H et al. Arch Intern Med. 2010;170(20):1850-5). 1 in 500 to 1 in 700 Caucasian individuals have this specific variant per a 1992 report by Rauh and colleagues. Tybjaerg-Hansen et al. (1998) found that the R3500Q mutation in the APOB gene is present in approximately 1 in 1,000 persons in Denmark and causes severe hypercholesterolemia and increases the risk of ischemic heart disease. Bednarska-Makaruk et al. (2001) found the arg3500-to-gln mutation in 2.5% (13/525) of unrelated patients with hypercholesterolemia in Poland. All the patients belonged to the type IIA hyperlipoproteinemia group. In 65 patients with the clinical characteristics of familial hypercholesterolemia, the frequency of the arg3500-to-gln mutation was 10.8% (7/65). The same haplotype at the APOB locus in the carriers of this mutation in Poland as in other populations from western Europe suggested its common origin. Horvath et al. (2001) studied 130 unrelated individuals with hypercholesterolemia in Bulgaria. Four of these individuals were found to be carriers of this mutation. Horvath et al. (2001) concluded that this mutation accounts for 0.99 to 8.17% (95% CI) of cases of hypercholesterolemia in Bulgaria and therefore represents the most common single mutation associated with this condition in Bulgaria. Segregation data is strong: Soria et al. (1989) demonstrated that this variant was found in 6 other, unrelated subjects and in 8 affected relatives in 2 of these families. A partial haplotype of this mutant apoB100 allele was constructed by sequence analysis and restriction enzyme digestion at positions where variations in the apoB100 are known to occur. This haplotype was found to be the same in 3 probands and 4 affected members of 1 family and lacks a polymorphic XbaI site whose presence has been correlated with high cholesterol levels. Tybjaerg-Hansen and Humphries (1992) gave a review suggesting that the risk of premature coronary artery disease in the carriers of the mutation is increased to levels as high as those seen in patients with familial hypercholesterolemia; at age 50, about 40% of males and 20% of females heterozygous for the mutation have developed coronary artery disease. Boren et al. (2001) concluded that normal receptor binding of LDL involves an interaction between arginine-3500 and tryptophan-4369 in the carboxyl tail of apoB100. Trp4369 to tyr (W4369Y) LDL and arg3500 to gln (R3500Q) LDL isolated from transgenic mice had identically defective LDL binding. Marz et al 1993 found that he arg3500-to-gln substitution profoundly alters the conformation of the apoB receptor binding domain when apolipoprotein B resides on particles at the lower and upper limits of the LDL density range. Marz et al in 1992 found that higher levels of apoE may be a compensatory mechanism whereby an increase in apoE leads to a decrease in LDL. The arginine at codon 3527 is completely conserved across species. Two alterations at the same codon, p.R3527L and p.R3527W (reported as p.R3500L and p.R3500W), have also been associated with FH (Gaffney D et al. Arterioscler. Thromb. Vasc. Biol. 1995;15:1025-9; Fouchier SW et al. Hum. Mutat. 2005;26:550-6). The variant was reported online in 63 of 122,754 individuals in the Genome Aggregation Consortium Dataset (gnomAD;, which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 58 of 55,525 individuals of European descent (MAF=0.05%), 1 of 11,148 individuals of Finnish descent, 1 of 16,779 individuals of Latino descent and 1 of 2,738 individuals of other descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. There is a cohort of patients with coronary artery disease in gnomAD. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012).

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