2-21006288-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 14P and 1B. PS1_ModeratePM2PM5PP5_Very_StrongBP4
The NM_000384.3(APOB):c.10580G>A(p.Arg3527Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000421 in 1,613,860 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3527L) has been classified as Pathogenic.
Frequency
Genomes: 𝑓 0.00069 ( 1 hom., cov: 33)
Exomes 𝑓: 0.00039 ( 0 hom. )
Consequence
APOB
NM_000384.3 missense
NM_000384.3 missense
Scores
7
4
5
Clinical Significance
Conservation
PhyloP100: 6.11
Genes affected
APOB (HGNC:603): (apolipoprotein B) This gene product is the main apolipoprotein of chylomicrons and low density lipoproteins (LDL), and is the ligand for the LDL receptor. It occurs in plasma as two main isoforms, apoB-48 and apoB-100: the former is synthesized exclusively in the gut and the latter in the liver. The intestinal and the hepatic forms of apoB are encoded by a single gene from a single, very long mRNA. The two isoforms share a common N-terminal sequence. The shorter apoB-48 protein is produced after RNA editing of the apoB-100 transcript at residue 2180 (CAA->UAA), resulting in the creation of a stop codon, and early translation termination. Mutations in this gene or its regulatory region cause hypobetalipoproteinemia, normotriglyceridemic hypobetalipoproteinemia, and hypercholesterolemia due to ligand-defective apoB, diseases affecting plasma cholesterol and apoB levels. [provided by RefSeq, Dec 2019]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 13 ACMG points.
PS1
Transcript NM_000384.3 (APOB) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr2-21006288-C-A is described in Lovd as [Pathogenic].
PP5
Variant 2-21006288-C-T is Pathogenic according to our data. Variant chr2-21006288-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-21006288-C-T is described in Lovd as [Pathogenic]. Variant chr2-21006288-C-T is described in Lovd as [Likely_pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.044617534). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| APOB | NM_000384.3 | c.10580G>A | p.Arg3527Gln | missense_variant | 26/29 | ENST00000233242.5 | NP_000375.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| APOB | ENST00000233242.5 | c.10580G>A | p.Arg3527Gln | missense_variant | 26/29 | 1 | NM_000384.3 | ENSP00000233242.1 |
Frequencies
GnomAD3 genomes 0.000690 AC: 105AN: 152104Hom.: 1 Cov.: 33
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GnomAD4 genome 0.000690 AC: 105AN: 152104Hom.: 1 Cov.: 33 AF XY: 0.000673 AC XY: 50AN XY: 74290
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:63Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypercholesterolemia, autosomal dominant, type B Pathogenic:21Other:2
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, University Hospital Schleswig-Holstein | Sep 30, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 02, 2023 | The APOB c.10580G>A (p.Arg3527Gln) missense variant, also reported as p.Arg3500Gln, results in the substitution of arginine at amino acid position 3527 with glutamine. The c.10580G>A variant 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 (PMID: 24404629). Across a selection of the available literature, the c.10580G>A variant has been found in a heterozygous state in 42 individuals with the disorder (PMID: 2563166; PMID: 9603795; PMID: 10952765; PMID: 11494965; PMID: 11781700; PMID: 26036859). Four of the studies demonstrated segregation of the variant with disease (PMID: 2563166; PMID: 10952765; PMID: 11494965; PMID: 26036859). Control data are unavailable for this variant, which is reported at a frequency of 0.000591 in the European (non-Finnish) population of the Genome Aggregation Database, which includes one homozygote (version 2.1.1) and at a frequency of 0.06798 in the Amish population (version 3.1.2), which is high but consistent with the prevalence of familial hypercholesterolemia in this population. Functional studies in transgenic mice showed that the variant resulted in defective LDL receptor binding (PMID: 11115503). Based on the available evidence, the c.10580G>A (p.Arg3527Gln) variant is classified as pathogenic for familial hypercholesterolemia. - |
| Likely pathogenic, no assertion criteria provided | research | deCODE genetics, Amgen | Jul 21, 2023 | The variant NM_000384.3:c.10580G>A (chr2:21006288) in APOB was detected in 3 heterozygotes out of 58K WGS Icelanders (MAF= 0,003%). Following imputation in a set of 166K Icelanders (8 imputed heterozygotes) we observed an association with LDL cholesterol using measurements from 128289 individuals (Effect (SD)= 1.89, P= 1.93e-03) and Non-HDL cholesterol using measurements from 136901 individuals (Effect (SD)= 1.85, P= 2.08e-03). This variant has been reported in ClinVar previously as likely pathogenic, pathogenic and as a variant of uncertain significance. Based on ACMG criteria (PS4, PM5, PP5) this variant classifies as likely pathogenic. - |
| Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 22, 2020 | The p.Arg3527Gln variant in APOB has been reported in at least 640 individuals with high LDL, segregated with disease in 6 affected relatives from 1 family (PMID: 28428224; doi:10.4172/2157-7412), and has been Identified in 0.05911% (76/128568) of European (non-Finnish) Chromosomes, and at lower frequencies in other populations, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs5742904). This variant has also been reported in ClinVar (VariationID: 17890) as likely pathogenic by 3 submitters, pathogenic by 16 submitters, and as a VUS by 1 submitter. Animal models in mice demonstrating decreased binding affinity of LDL for its receptor have shown that this variant causes high LDL (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. Multiple variants in the same region as p.Arg3527Gln variant have been reported in association with disease in ClinVar and the literature and the variant is located in a region of APOB that is essential to normal receptor binding, suggesting that this variant is in a hot spot and functional domain and supports pathogenicity (PMID: 9486979; Variation ID: 40223, 440523). The two additional pathogenic and likely pathogenic variants, resulting in a different amino acid change at the same position, p.Arg3527Trp and p.Arg3527Leu, have been reported in association with the disease in the literature and ClinVar, supporting that a change at this position may not be tolerated (VariationID: 40223, 440523). In summary, this variant meets criteria to be classified as pathogenic for high LDL in an autosomal dominant manner based on the prevalence of the variant in affected individuals and relatives, the reports that the variant is essential for normal receptor binding, and mouse models demonstrating the variant to be causative of disease. ACMG/AMP Criteria applied: PS4, PM5, PM1, PS3_moderate, PP1_moderate, PP3 (Richards 2015). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | Oct 17, 2019 | This variant has been previously reported as heterozygous change in patients with hypercholesterolemia (PMID: 9105560, 21059979, 18325181, 18222178, 10388479, 23375686, 2563166, 21868016). Experimental studies have shown that this missense change disturbs the APOB protein conformation, therefore reducing its ability to act as inhibitor of the LDL receptor (PMID: 11115503, 15797858). This variant is also known in the literature as p.Arg3500Gln (PMID: 27919345). ClinVar contains an entry for this variant (Variation ID: 17890). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.03% (83/282162), and one homozygous individual is also reported. The c.10580G>A (p.Arg3527Gln) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.10580G>A (p.Arg3527Gln) variant is classified as Pathogenic. - |
| not provided, no classification provided | phenotyping only | GenomeConnect - Brain Gene Registry | - | Variant classified as Pathogenic and reported on 02-16-2021 by The Children's Hospital of Philadelphia. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2001 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 22, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Apr 07, 2021 | PS3, PP1_Strong, PP3, PM5 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | May 25, 2017 | 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 (http://exac.broadinstitute.org/variant/2-21229160-C-T). 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Division of Medical Genetics, University of Washington | Mar 07, 2020 | This is a well-studied variant in the APOB gene and has been shown to cause hypercholesterolemia via apolipoprotein B deficiency (Soria 1989, Tybjaerg-Hansen 1998). This variant has bene observed in a number of individuals and families with FH (Garcia-Garcia 2011, Radovica-Splavina 2015, Shen 2010, Soria 1989) and functional studies have demonstrated that this variant results in decreased low density lipoprotein (LDL) binding affinity (Benn 2005, Boren 2001). Based on this evidence, we consider this variant to be pathogenic. PS4; PP1; PS3 - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Nov 05, 2024 | Criteria applied: PS3,PS4,PM5_STR,PP1,PP3 - |
| Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Sep 01, 2020 | ACMG codes:PS3,PS4,PM2,PM5,PP3 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Jul 12, 2023 | The APOB c.10580G>A variant is classified as Pathogenic (PS4, PS3, PP1_Strong, PP3) The APOB c.10580G>A variant is a single nucleotide change in exon 26/29 of the APOB gene, which is predicted to change the amino acid arginine at position 3527 in the protein to glutamine. This variant is a well-known cause of hypercholesterolemia due to defective ApoB mainly in people of European ancestry and is reported as an Amish founder variant (PMID: 24404629). This variant has been reported in multiple unrelated affected individuals (PMID: 21059979) and with low allele frequency in gnomAD population data, demonstrating that this variant is enriched in the disease population (PS4). Note that this variant has also been reported as R3500Q in the literature. A paper by Soria et. al, 1989 (PMID: 2563166) reports segregation with disease in 2 families (PP1_strong). Functional assays have demonstrated that this missense variant disturbs the APOB protein conformation preventing it from binding LDL, disturbing its normal function as inhibitor of the LDL receptor (PMID: 11115503) (PS3). Computational predictions (REVEL = 0.735) support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs5742904) and in the HGMD database: CM890006. It has been reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 17890). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | - | - - |
| Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Mar 28, 2018 | ACMG codes: PS3, PS4, PP1, PP3, PP5 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Mar 30, 2023 | This sequence change in APOB is predicted to replace arginine with glutamine at codon 3527, p.(Arg3527Gln). The arginine residue is highly conserved (100 vertebrates, UCSC), and is a critical residue for normal LDL receptor binding (PMID: 9486979). There is a small physicochemical difference between arginine and glutamine. The highest population minor allele frequency in gnomAD v2.1 is 0.06% (76/128,568 alleles, 1 homozygote) in the European (non-Finnish) population. This is the most commonly occurring variant identified in European APOB-related familial hypercholesterolaemia individuals (PMID: 24404629). The variant has been reported to segregate with familial hypercholesterolaemia in multiple families (PMID: 2563166, 26036859). Assessment of the whole LDL receptor cycle in heterologous cells showed defective LDL receptor-binding activity indicating that this variant impacts protein function (PMID: 9486979, 11115503 ). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PS3, PP1_Strong, PM1, PP3. - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 27, 2024 | This missense variant replaces arginine with glutamine at codon 3527 in the beta 2 domain of the APOB protein. This variant is also known as p.Arg3500Gln in the mature protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. Functional studies have shown that the variant affects 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, 32591292, 35052492, 35741760, 37593691) 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, is known to be pathogenic (ClinVar variation ID 40223), indicating that arginine at this position is important for APOB protein function. This variant has been identified in 83/282162 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; 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 the available evidence, this variant is classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Immunology and Genetics Kaiserslautern | Mar 21, 2023 | ACMG Criteria: PS3, PS4, PM1, PM5, PP1, PP3, PP4, PP5; Variant was found in heterozygous state. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Region Ostergotland | Oct 27, 2023 | PS4, PP1, PP3, PS3 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Sep 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with familial hypercholesterolaemia, 2 (MIM#144010) and hypobetalipoproteinaemia (MIM#615558). (I) 0108 - This gene is associated with both recessive and dominant disease. Familial hypercholesterolaemia 2 (MIM#144010) is inherited in an autosomal dominant manner, whereas hypobetalipoproteinaemia (MIM#615558) is recessive (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 24404629). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 (103 heterozygotes, 1 homozygote). This includes 62 heterozygotes from the Amish sub-population, in which this variant is known to be a founder mutation (PMID: 35300601). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (45 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Arg3527Trp) has been classified as pathogenic by multiple clinical laboratories in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic and likely pathogenic by multiple clinical laboratories in ClinVar and is well reported to cause familial hypercholesterolaemia (PMID: 35300601). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Medicine Lab, University of California San Francisco | Aug 16, 2023 | - - |
not provided Pathogenic:15
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2024 | APOB: PP1:Strong, PM1, PM2, PM5, PS4:Moderate, PS3:Supporting - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 26, 2023 | The APOB c.10580G>A; p.Arg3527Gln variant (rs5742904), also reported as Arg3500Gln, is described in the literature in many affected individuals, reported to segregate with disease in affected families, and is one of the most common variants associated with familial hypercholesterolemia in individuals of European ancestry (Braenne 2016, Horvath 2001, Peloso 2014, Tybjaerg-Hansen 1998, Youngblom 2016). The variant is reported as pathogenic by many sources in the ClinVar database (Variation ID: 17890) and is found in the non-Finnish European population with an allele frequency of 0.06% (76/128,568 alleles including 1 homozygote) in the Genome Aggregation Database. The arginine at codon 3527 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL:0.735). In support of this prediction, functional studies show that the variant results in defective LDL binding (Boren 2001). Based on available information, this variant is considered to be pathogenic. References: Boren J et al. The molecular mechanism for the genetic disorder familial defective apolipoprotein B100. J Biol Chem. 2001 Mar 23;276(12):9214-8. PMID: 11115503. Braenne I et al. Systematic analysis of variants related to familial hypercholesterolemia in families with premature myocardial infarction. Eur J Hum Genet. 2016 Feb;24(2):191-7PMID: 26036859. Horvath A et al. High frequency of the ApoB-100 R3500Q mutation in Bulgarian hypercholesterolaemic subjects. J Med Genet. 2001 Aug;38(8):536-40. PMID: 11494965. Peloso GM et al. Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks. Am J Hum Genet. 2014 Feb 6;94(2):223-32. PMID: 24507774. Tybjaerg-Hansen A et al. Association of mutations in the apolipoprotein B gene with hypercholesterolemia and the risk of ischemic heart disease. N Engl J Med. 1998 May 28;338(22):1577-84. PMID: 9603795. Youngblom E et al. Familial Hypercholesterolemia. 2014 Jan 2 (updated 2016 Dec 8). In: Adam MP et al, editors. GeneReviews (Internet). Seattle (WA): University of Washington, Seattle; 1993-2021. PMID: 24404629. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Apr 18, 2023 | PP1_STR, PP3, PM5, PS3 - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Apr 18, 2016 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Nov 18, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Oct 12, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 24, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 17, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 10, 2020 | Also denoted as R3500Q due to the use of alternate nomenclature; Functional studies indicate that the R3527Q variant causes decreased binding of the APOB protein to the LDL receptor (Fisher et al., 1999); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26643808, 26036859, 26415676, 22859806, 31028937, 24106285, 24507774, 20736250, 18325181, 21868016, 9105560, 18222178, 21919778, 15797858, 2563166, 24956927, 8318993, 10388479, 23375686, 26636822, 27497240, 27872105, 27831900, 27824480, 28502510, 27765764, 28104544, 9259199, 21382890, 30030251, 29555771, 28965616, 27784735, 28428224, 9603795, 30122538, 30592178, 30270359, 31106297, 29284604, 30291343, 32591292, 31447099, 31980526, 34040191, 34570182, 11238294, 21059979, 34037665, 33303402, 32719484, 32522009, 33740630, 33111339, 33418990, 33269076, 1892487, 2067318, 32770674, 33069457) - |
| Pathogenic, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | May 16, 2017 | 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; http://gnomad.broadinstitute.org/), whi - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 08, 2022 | The APOB c.10580G>A (p.Arg3527Gln) variant has been reported in the published literature in several individuals and families affected with hypercholesterolemia (PMIDs: 2563166 (1989), 9603795 (1998), 10388479 (1999), 23375686 (2013), 24404629 (2016), 31345425 (2019)). It has been reported to be strongly associated with disease in families affected with hypercholesterolemia (PMIDs: 2563166 (1989), 21868016 (2011)) and has been reported as a founder mutation in the Amish community (PMID: 21059979 (2010)). Published functional studies demonstrate that this variant is damaging to LDL receptor binding (PMIDs: 10388479 (1999), 11115503 (2001)). Based on the available information, this variant is classified as pathogenic. - |
Hypercholesterolemia, familial, 1 Pathogenic:9
| Likely pathogenic, criteria provided, single submitter | research | Institute for Integrative and Experimental Genomics, University of Luebeck | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jun 09, 2022 | - - |
| Pathogenic, criteria provided, single submitter | research | Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia | May 23, 2019 | - - |
| Pathogenic, criteria provided, single submitter | research | Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge | Mar 01, 2016 | 0/190 non-FH alleles - |
| Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
| Pathogenic, criteria provided, single submitter | research | Fundacion Hipercolesterolemia Familiar | Mar 01, 2016 | - - |
| Pathogenic, criteria provided, single submitter | research | Laboratory of Genetics and Molecular Cardiology, University of São Paulo | Mar 01, 2016 | - - |
| Pathogenic, criteria provided, single submitter | research | Iberoamerican FH Network | Mar 01, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Robarts Research Institute, Western University | Aug 22, 2019 | - - |
Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1 Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Sep 16, 2022 | The c.10580G>A variant has previously been reported in multiple individuals with familial hypercholesterolemia [PMID: 24404629] and has been shown to segregate with hypercholesterolemia in multiple families [PMID: 2563166, 8254047, 21868016]. This variant is reported as one of the two most common variants associated with familial hypercholesterolemia, particularly in individuals of European ancestry [PMID: 24404629]. Multiple independent laboratories have deposited this variant as Pathogenic/Likely Pathogenic in the ClinVar database (Variation ID: 17890). The c.10580G>A variant is observed in 328 alleles (0.0556% minor allele frequency with 5homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8). This frequency is low enough to be consistent with the frequency of familial hypercholesterolemia in the general population and pathogenic variants in APOB can have reduced penetrance and a less severe phenotype than disease-causingLDLR or PCSK9 variants [PMID: 24404629]. The c.10580G>A variant is located in exon 26 of this 29-exon gene and is predicted to replace an evolutionarilyconserved arginine amino acid with glutamine at position 3527 in the encoded protein. In silico predictions are in favor of damaging effect for p.(Arg3527Gln) variant [(CADD v1.6 = 28, REVEL = 0.735)]. Functional studies have demonstrated that this variant affects APOB protein conformation and impairs its binding to the LDLR protein [PMID: 8254047, 9486979, 10388479, 11115503, 15797858, 26643808]. A different amino acid change at this codon p.(Arg3527Gln) has been reported in ClinVar [ClinVar ID: 40223] as Pathogenic. Moreover, a different missense variant p.(Arg3527Leu) has been reported in individuals with familial hypercholesterolemia [PMID:16250003, 33269076]. Based on available evidence this c.10580G>A p.(Arg3527Gln) variant identified in APOB is classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 30, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 3527 of the APOB protein (p.Arg3527Gln). This variant is present in population databases (rs5742904, gnomAD 0.06%). This missense change has been observed in individual(s) with hypercholesterolemia (PMID: 2563166, 9105560, 10388479, 18222178, 18325181, 21059979, 21868016, 23375686, 24404629). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17890). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on APOB protein function. Experimental studies have shown that this missense change affects APOB function (PMID: 11115503, 15797858). This variant disrupts the p.Arg3527 amino acid residue in APOB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7627691). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Heidelberg University | Aug 02, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 22, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PS4+PS3+PM2_Supporting+PP1_Strong - |
Familial hypercholesterolemia Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health | Aug 06, 2021 | - - |
| Likely pathogenic, criteria provided, single submitter | research | Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 10, 2017 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 10, 2024 | This missense variant (also known as p.Arg3500Gln) is located in the beta 2 domain of the APOB protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. Functional studies have shown that the variant affects 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, 32591292, 35052492, 35741760, 37593691) 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, is known to be pathogenic (ClinVar variation ID 40223), indicating that arginine at this position is important for APOB protein function. This variant has been identified in 83/282162 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; 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 the available evidence, this variant is classified as Pathogenic. - |
Familial hypobetalipoproteinemia 1 Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 22, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Nov 11, 2020 | - - |
| Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Aug 21, 2019 | - - |
APOB-related disorder Pathogenic:2
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 31, 2024 | The APOB c.10580G>A variant is predicted to result in the amino acid substitution p.Arg3527Gln. This variant was identified and characterized in the 1980s (aka p.Arg3500Gln, Innerarity et al. 1987. PubMed ID: 3477815; Soria et al. 1989. PubMed ID: 2563166). It is now recognized as the most common pathogenic variant in APOB for autosomal dominant familial hypercholesterolemia (reviewed by Varret et al. 2008. PubMed ID: 18028451). The p.Arg3527Gln substitution has been shown to reduce the binding affinity of LDL receptors to 30% of normal values (Innerarity et al. 1987. PubMed ID: 3477815). This variant is reported in 0.059% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | - | This variant is also known in the literature as p.Arg3500Gln (PMID: 27919345). This variant has been previously reported as heterozygous change in patients with hypercholesterolemia (PMID: 9105560, 21059979, 18325181, 18222178, 10388479, 23375686, 2563166, 21868016). Experimental studies have shown that this missense change disturbs the APOB protein conformation, therefore reducing its ability to act as inhibitor of the LDL receptor (PMID: 11115503, 15797858). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.03% (83/282162), and one homozygous individual is also reported. The c.10580G>A (p.Arg3527Gln) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.10580G>A (p.Arg3527Gln) variant is classified as Pathogenic. - |
Homozygous familial hypercholesterolemia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 02, 2020 | The p.Arg3527Gln variant in APOB is a well-established pathogenic variant that is mainly found in individuals of European descent. It has been previously reported in >500 individuals with familial hypercholesterolemia (FH) and segregated with disease in >50 affected relatives (Soria 1989 PMID: 2563166, März 1993 PMID: 8254047, Leren 1997 PMID: 9104431, Ludwig 1990 PMID: 1977310, Bednarska-Makaruk 2001 PMID: 11781700, Horvath 2001 PMID: 11494965, Kalina 2001 PMID: 11137107). It has also been reported by other clinical laboratories in ClinVar (Variation ID 17890) and has been identified in 0.06% (76/128568) of European chromosomes, including 1 homozygote, by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This frequency is low enough to be consistent with the frequency of FH in the general population. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant familial hypercholesterolemia based upon presence in multiple affected individuals and segregation studies. 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. - |
See cases Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Mar 22, 2022 | ACMG categories: PM2,PM5,PP3,PP5 - |
Hypobetalipoproteinemia Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 30, 2015 | - - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 03, 2022 | The p.R3527Q pathogenic mutation (also known as c.10580G>A), located in coding exon 26 of the APOB gene, results from a G to A substitution at nucleotide position 10580. The arginine at codon 3527 is replaced by glutamine, an amino acid with highly similar properties. This alteration (also reported as p.R3500Q) was initially reported in seven unrelated probands with familial hypercholesterolemia (FH) and found to segregate with disease in two families (Soria et al. Proc Natl Acad Sci USA. 1989; 86(2):587-91). This pathogenic mutation 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). In addition, this alteration has been reported to result in defective low-density lipoprotein receptor binding (Boren J et al. J Clin Invest. 1998;101(5):1084-93). 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). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Uncertain
D
PrimateAI
Benign
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Pathogenic
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at