ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.798T>A (p.Asp266Glu) (rs139043155)

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Total submissions: 27
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER _CC_NCGL, University of Washington RCV000148594 SCV000190309 uncertain significance Hypercholesterolaemia 2014-06-01 criteria provided, single submitter research Low GERP score may suggest that this variant may belong in a lower pathogenicity class
Institute for Integrative and Experimental Genomics,University of Luebeck RCV000172959 SCV000212134 likely benign Familial hypercholesterolemia 1 criteria provided, single submitter research
GeneDx RCV000162020 SCV000234646 pathogenic not provided 2020-11-10 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Published functional studies classify D266E as partially transport-defective with LDL receptor activity at 15-30% (Hobbs et al., 1992); Disrupts a negatively charged triplet, Ser-Asp-Glu, located at the carboxyl-terminal end of the LDL-receptor class A6 repeat domain that is critical for ligand binding (Schneider et al., 2003); Reported in ClinVar (ClinVar Variant ID#161287; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 24014831, 25637381, 27824480, 20145306, 23375686, 25487149, 26036859, 25647241, 1301956, 22698793, 26892515, 22881376, 15556092, 23064986, 11052664, 11524740, 28008010, 24507775, 23833242, 27596133, 29083407, 30795984, 31401775, 31447099, 32041611, 32719484, 33269076, 32770674)
LDLR-LOVD, British Heart Foundation RCV000172959 SCV000294979 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000172959 SCV000484680 likely pathogenic Familial hypercholesterolemia 1 criteria provided, single submitter clinical testing
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000172959 SCV000503238 likely pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 4 , family members = 11 with co-segregation / FH-Cincinnati-1, 15 to 30% LDLR activity / Software predictions: Damaging
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000172959 SCV000540759 likely pathogenic Familial hypercholesterolemia 1 2016-11-05 criteria provided, single submitter clinical testing
Invitae RCV000791360 SCV000544696 pathogenic Familial hypercholesterolemia 2020-10-30 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glutamic acid at codon 266 of the LDLR protein (p.Asp266Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant has been reported in many unrelated individuals affected with hypercholesterolemia (PMID: 1301956, 23375686, 21310417) and is established as a common cause of disease (PMID: 20663204, 22698793, 26238499). This variant is also known as p.Asp245Glu in the literature. ClinVar contains an entry for this variant (Variation ID: 161287). A different missense substitution at this codon (p.Asp266Tyr) is reported to be deleterious (PMID: 11196104). This indicates that the asparagine residue is important for LDLR protein function. For these reasons, this variant has been classified as Pathogenic.
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000172959 SCV000583741 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000172959 SCV000590848 likely pathogenic Familial hypercholesterolemia 1 2015-09-10 criteria provided, single submitter clinical testing
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000172959 SCV000599348 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter curation
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000844745 SCV000711397 pathogenic Homozygous familial hypercholesterolemia 2020-11-15 criteria provided, single submitter clinical testing The p.Asp266Glu variant (also described as p.Asp245Glu in the literature) has been reported in over 100 individuals with familial hypercholesterolemia (FH; Bertolini 2013 PMID: 23375686, Brænne 2015 PMID: 26036859, Brusgaard 2006 PMID: 16542394, Chmara 2010 PMID: 20145306, Do 2015 PMID: 25487149, Fouchier 2001 PMID: 11810272, Hobbs 1992 PMID: 1301956, Schmidt 2000 PMID: 10657581, Sharifi 2016 PMID: 26892515, Tichý 2012 PMID: 22698793, Weiss 2000 PMID: 11196104) and reportedly segregated with disease in numerous affected relatives from multiple families (Clinvar, Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation SCV000540759.1). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 161287) and has been identified in 0.008% (10/129194) of European chromosomes by gnomAD ( This frequency is low enough to be consistent with the frequency of FH in the general population. In vitro functional studies provide some evidence that the p.Asp266Glu variant may impact protein function, resulting in 15-30% LDL receptor activity (Hobbs 1992 PMID: 1301956). Computational prediction tools and conservation analysis suggest that the p.Asp266Glu variant may impact the protein. Another likely pathogenic missense change at the same position (p.Asp266Tyr) has been reported in association to FH (reported as p.Asp245Tyr, Weiss 2000 PMID: 11196104). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PS4, PP1_Moderate, PM5_Supporting, PM2_Supporting , PP3, PS3_supporting.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000172959 SCV000839980 likely pathogenic Familial hypercholesterolemia 1 2017-07-06 criteria provided, single submitter clinical testing This c.798T>A (p.Asp266Glu) variant has previously been detected in multiple patients with familial hypercholesterolemia [PMID 1301956, 11196104, 25637381, 25487149, 11810272, 16542394, 21310417, also reported as FH Cincinnati-1 (legacy: 245)]. Additional patients with hypercholesterolemia have been reported with variants located at the same amino acid position (p.Asp266Asn, p.Asp266Gly, p.Asp266Tyr and p.Asp266Val). This variant was observed in ten heterozygous individuals in the gnomAD database ( This variant is highly conserved in mammals and computer-based algorithms predict this p.Asp266Glu change to be deleterious. It is thus classified as likely pathogenic.
Department of Human Genetics,Laborarztpraxis Dres. Walther, Weindel und Kollegen RCV000172959 SCV000987028 likely pathogenic Familial hypercholesterolemia 1 2017-10-30 criteria provided, single submitter clinical testing The nucleotide substitution c.798T>A causes an exchange of the amino acid aspartate acid to glutamate at position 266 (p.Asp266Glu, D266E). This mutation has already been described in patients with hypercholesterolemia and is therefore classified as pathogenic. PMID: 1301956, 11810272, 16542394
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000172959 SCV000996264 likely pathogenic Familial hypercholesterolemia 1 2019-03-13 criteria provided, single submitter clinical testing This variant has been previously reported as a heterozygous change in patients with familial hypercholesterolemia or early-onset myocardial infarction (PMID: 23375686, 25487149). Functional studies by Hobbs et al. (PMID 1301956) demonstrated that LDL receptor activity in patients with the p.Asp266Glu variant is 15-30% of wild type allele. This change is reported in ClinVar by other clinical laboratories (Variation ID 161287), as well as described as disease causing variant in the Human Disease Mutation Database. It is present in the heterozygous state in the gnomAD population database at a frequency of 0.004% (10/277250) and thus is presumed to be rare. In silico analyses support a deleterious effect of the c.798T>A (p.Asp266Glu) variant on protein function. Based on the available evidence, the c.798T>A (p.Asp266Glu) variant is classified as likely pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000162020 SCV001246006 pathogenic not provided 2021-04-01 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000172959 SCV001251400 pathogenic Familial hypercholesterolemia 1 2021-04-07 criteria provided, single submitter clinical testing
Color Health, Inc RCV000791360 SCV001355074 pathogenic Familial hypercholesterolemia 2020-03-05 criteria provided, single submitter clinical testing
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia RCV000172959 SCV001432578 likely pathogenic Familial hypercholesterolemia 1 2019-06-04 criteria provided, single submitter research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000791360 SCV001442758 pathogenic Familial hypercholesterolemia 2020-10-08 criteria provided, single submitter clinical testing Variant summary: LDLR c.798T>A (p.Asp266Glu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251482 control chromosomes. c.798T>A has been widely reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (example, Hobbs_1992, Tichy_2012, Goldmann_2010, Duskova_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Hobbs_1992). The most pronounced variant effect results in 15%-30% of normal LDL receptor activity. Seventeen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely pathogenic/pathogenic, n=16). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory of Molecular Genetics,National Medical Research Center for Therapy and Preventive Medicine RCV000791360 SCV001482460 uncertain significance Familial hypercholesterolemia criteria provided, single submitter research
Mayo Clinic Laboratories, Mayo Clinic RCV000162020 SCV001715242 pathogenic not provided 2020-07-02 criteria provided, single submitter clinical testing PS3, PS4_moderate, PM1, PM2, PM5, PP3
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000162020 SCV000189623 not provided not provided no assertion provided in vitro
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000172959 SCV000268586 pathogenic Familial hypercholesterolemia 1 2008-07-09 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000172959 SCV000606226 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000162020 SCV000925128 pathogenic not provided 2016-10-19 no assertion criteria provided provider interpretation The patient had genetic testing for the familial hypercholesterolemia panel with Ambry Genetics. The test included sequencing of three genes associated with familial hypercholesterolemia: LDLR, APOB and PCSK9. Results showed that the following variant was identified (see report below): p.Asp266Glu (c.798T>A) in the LDLR gene (NM_000527.4) The lab classifies this variant as likely pathogenic. Given sufficient case data we consider this variant likely pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in more than 20 unrelated cases of familial hypercholesterolemia (not including this patient's family). This variant is also reported in the literature as p.Asp245Glu (c.798T>A). Hobbs, et al. 1992 first reported this variant in his cohort of patients with FH. The patient was diagnosed with hyperlipidemia type 2B (FH), and had 15-30 % of residual LDLR activity. Schmidt, et al. 2000 reported this variant in 16 unrelated index cases in Australia. They were all clinically diagnosed with familial hypercholesterolemia and is one of the most common variants identified in his Australian cohort of 950 index cases. Fouchier SW et al. 2001 identified this variant and a similar variant at the same position, D245N, in his cohort. Brusgaard, et al. 2006 also reported this variant in three individuals who had a clinical diagnosis of familial hypercholesterolemia. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (HumVar: 0.998). The aspartic acid at codon 266 is conserved across species, as are some neighboring amino acids. Other variants have been reported in association with disease at this codon (D245N). There are two individuals with variation at codon 266 listed in the Exome Aggregation Consortium dataset (, which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of October 10, 2016). The average coverage at that site in ExAC is 40x.
Clinical Genetics,Academic Medical Center RCV000162020 SCV001923193 pathogenic not provided no assertion criteria provided clinical testing

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