ClinVar Miner

Submissions for variant NM_000384.3(APOB):c.10579C>T (p.Arg3527Trp) (rs144467873)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 15
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000627798 SCV000284754 pathogenic Familial hypercholesterolemia 2; Hypobetalipoproteinemia, familial, 1 2020-10-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 3527 of the APOB protein (p.Arg3527Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs144467873, ExAC 0.1%). This variant has been observed in several individuals and families affected with familial hypercholesterolemia (FH) (PMID: 7627691, 9191540, 9702952, 22294733, 21376320, 16250003, 11238294). This variant is a common cause of FH in individuals of East Asian ancestry (PMID: 9702952, 27206935), but has also been reported in individuals of other ancestries (PMID: 23936638, 16250003, 23375686, 26415676). This variant is also known as R3500W in the literature. ClinVar contains an entry for this variant (Variation ID: 40223). Experimental studies have shown that this sequence change has been shown to affect protein function (PMID: 11238294, 10388479). In addition, a different missense substitution at this codon (p.Arg3527Gln) is reported to be deleterious (PMID: 24234650, 2563166). This indicates that the arginine residue is important for APOB protein function. In summary, this missense variant has been reported in affected individuals and affects a residue which is important for APOB protein function. For these reasons it has been classified as Pathogenic.
Robarts Research Institute,Western University RCV000408839 SCV000484822 pathogenic Familial hypercholesterolemia 1 2019-08-22 criteria provided, single submitter clinical testing
GeneDx RCV000494148 SCV000583115 pathogenic not provided 2018-06-07 criteria provided, single submitter clinical testing The R3527W variant in the APOB gene has been reported previously in association with hypercholesterolemia using alternate nomenclature, R3500W (Gaffney et al., 1995; Tai et al., 1998; Fisher et al., 1999). The R3527W variant is observed in 11/8642 (0.1%) alleles from individuals of East Asian background in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R3527W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. Functional studies demonstrated the R3500W variant reduced APOB capacity for binding, uptake and degradation of LDL (Fisher et al., 1999). Furthermore, a different missense variant affecting the same residue (R3527Q) has been reported in the Human Gene Mutation Database in association with an APOB-related disorder (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret R3527W as a pathogenic variant.
Fundacion Hipercolesterolemia Familiar RCV000408839 SCV000607383 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000844613 SCV000712357 pathogenic Homozygous familial hypercholesterolemia 2020-11-02 criteria provided, single submitter clinical testing The p.Arg3527Trp variant (also referred to in the literature as p.Arg3500Trp) in APOB has been reported in at least 33 individuals with familial hypercholesterolemia, the majority of whom are of East Asian ancestry, and segregated with disease in at least 15 affected relatives from 4 families (Gaffney 1995 PMID: 7627691, Choong 1997 PMID: 9191540, Tai 1998 PMID: 9702952, Fisher 1999 PMID: 10388479, Tai 2001 PMID: 11238294, Yang 2007 PMID: 17964958, Hollandt 2012 PMID: 22294733, Chiou 2010 PMID: 20538126, Chiou 2011 PMID: 21376320, Chiou 2012 PMID: 22353362, Bertolini 2013 PMID: 23375686). This variant has been reported in ClinVar (Variation ID 40223) and has also been identified in 0.12% (25/19946) of East Asian and 0.007% (25/128542) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of familial hypercholesterolemia (FH) in the general population. In vitro functional studies provide some evidence that the p.Arg3527Trp variant may impact protein function (Gaffney 1995 PMID: 7627691, Fisher 1999 PMID: 10388479, Tai 2001 PMID: 11238294). Additionally, another variant at this position, p.Arg3527Gln, is a well-established pathogenic variant for FH. In summary, this variant meets criteria to be classified as pathogenic for FH in an autosomal dominant manner based upon segregation studies, increased prevalence in affected individuals, and pathogenicity of other variants at this position. Please note that pathogenic variants in APOB can have reduced penetrance and a less severe phenotype than disease-causing LDLR or PCSK9 variants (Youngblom and Knowles, GeneReviews, PMID: 24404629). ACMG/AMP Criteria applied: PS4_Strong; PP1_Strong, PS3_Supporting, PM5.
Illumina Clinical Services Laboratory,Illumina RCV000231844 SCV000914259 pathogenic Familial hypercholesterolemia 2 2019-04-05 criteria provided, single submitter clinical testing Across a selection of the available literature, the APOB c.10579C>T (p.Arg3527Trp) missense variant, previously reported in the literature as p.Arg3500Trp, has been identified in a heterozygous state in at least 33 individuals with familial hypercholesterolemia, 15 of whom were unrelated (Gaffney et al. 1995; Choong et al. 1997; Tai et al. 1998; Fisher et al. 1999). The p.Arg3527Trp variant was absent from 309 controls and is reported at a frequency of 0.001273 in the East Asian population of the Exome Aggregation Consortium. Arg3527 is located in the LDL receptor-binding domain of the APOB protein. Fisher et al. (1999) demonstrated in human skin fibroblast cells that the p.Arg3527Trp variant protein had lower rates of binding, internalization, and degradation of LDL than wild type levels. Based on the evidence, the p.Arg3527Trp variant is classified as pathogenic for familial hypercholesterolemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780859 SCV000918477 pathogenic Familial hypercholesterolemia 2018-07-31 criteria provided, single submitter clinical testing Variant summary: APOB c.10579C>T (p.Arg3527Trp also known as R3500W) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 276418 control chromosomes (gnomAD). c.10579C>T has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Chiou_2012, Wald_2016). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic" (4x) and once as "uncertain significance." Based on the evidence outlined above, the variant was classified as pathogenic.
Color Health, Inc RCV000780859 SCV001347007 pathogenic Familial hypercholesterolemia 2020-08-24 criteria provided, single submitter clinical testing This missense variant (also known as p.Arg3500Trp) is located in the beta 2 domain of the APOB protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant diminishes binding, uptake and degradation of LDL (PMID: 7627691, 10388479, 11238294). This variant has been reported in numerous individuals affected with familial hypercholesterolemia in multiple populations, the majority being of East Asian ancestry, and has been shown to segregate with the disorder in multiple families (PMID: 7627691, 9191540, 9702952, 10388479, 11238294, 16250003, 21376320, 22294733, 23375686, 23936638, 27206935). A different missense variant at the same position, p.Arg3527Gln, is a well established pathogenic variant (Clinvar variation ID 17890). This variant has been identified in 40/276418 chromosomes in the general population by the Genome Aggregation Database (gnomAD). APOB mutations show incomplete penetrance and individuals with APOB mutations may show a less severe phenotype than familial hypercholesterolemia patients with LDLR mutations (PMID: 8141833, 21868016, 21513517). 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.
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia RCV000408839 SCV001432580 likely pathogenic Familial hypercholesterolemia 1 2019-03-18 criteria provided, single submitter research
Johns Hopkins Genomics, Johns Hopkins University RCV000231844 SCV001573163 pathogenic Familial hypercholesterolemia 2 2021-04-05 criteria provided, single submitter clinical testing The c.10579C>T variant in APOB is one of the most frequent genetic changes reported in individuals with familial hypercholesterolemia-2 (FCHL2), a condition characterized by very high levels of cholesterol in the blood and an increased risk of developing heart disease, beginning at 40 to 50 years of age. However, reduced penetrance of FCHL2 has been reported in persons with a heterozygous APOB pathogenic variant. This variant (rs144467873) is rare in a large population database (45/282118 total alleles; 0.016%; no homozygotes) and has an entry in ClinVar. Experiments using patient derived skin fibroblast cells that contain the p.Arg3527Trp variant protein had lower rates of binding, internalization, and degradation of LDL than wild type levels. In addition, the proliferation rate of U937 cells containing the p.Arg3527Trp substitution supplied with LDL was fourfold less than wild type controls. We consider this variant to be pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000494148 SCV001713960 pathogenic not provided 2020-08-26 criteria provided, single submitter clinical testing
GeneReviews RCV000231844 SCV000490149 pathogenic Familial hypercholesterolemia 2 2016-12-08 no assertion criteria provided literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000408839 SCV000605967 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Molecular Genetics Laboratory,BC Children's and BC Women's Hospitals RCV000494148 SCV000803730 pathogenic not provided 2018-05-03 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000231844 SCV001422753 pathogenic Familial hypercholesterolemia 2 2020-01-22 no assertion criteria provided curation The p.Arg3527Trp variant in APOB has been reported in at least 47 individuals with hypercholesterolemia, segregated with disease in 10 individuals from 2 families (PMID: 27206935, 17087781, 20538126), and has been identified in 0.1253% (25/19946) of East Asian chromosomes, 0.03594% (11/30604) of South Asian chromosomes, and 0.007002% (9/128542) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs144467873). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Animal models in mice have shown that this variant causes hypercholesterolemia (PMID: 9486979). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Two additional pathogenic/likely pathogenic variants, resulting in a different amino acid change at the same position, p.Arg3527Gln and p.Arg3527Leu, have been reported in association with hypercholesterolemia in the literature and ClinVar, supporting that a change at this position may not be tolerated (VariationID: 17890, 440523; PMID: 9486979, 23369702, 28428224). Additionally, the p.Arg3527Trp variant is located in a region of APOB that is essential to protein folding and stability, suggesting that this variant is a functional domain and supports pathogenicity (PMID: 9486979). In summary, this variant meets criteria to be classified as pathogenic for hypercholesterolemia in an autosomal dominant manner based on prevalence of the variant and cosegregation in affected individuals, the location of the variant in a functional domain, and animal models demonstrating a deficient protein. ACMG/AMP Criteria applied: PS4, PP11_strong, PM5, PM1, PS3_moderate, PP3 (Richards 2015).

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.