ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.301G>A (p.Glu101Lys) (rs144172724)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 17
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000775032 SCV000285028 pathogenic Familial hypercholesterolemia 2018-11-15 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 101 of the LDLR protein (p.Glu101Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs144172724, ExAC <0.01%). This variant has been reported in the literature to segregate with disease in two families (PMID: 1301940, 1352322) and also present in multiple individuals affected with hypercholesterolemia (PMID: 1352322, 11668627, 23669246, 18718593, 19843101, 15241806, 20236128, 17142622, 16314194, 11668640). This variant is also known in the literature as E80K. ClinVar contains an entry for this variant (Variation ID: 161266). One experimental study has shown that this missense variant inhibited LDL uptake in Hel-Kyoto cells (PMID: 25647241). In summary, this variant is present at a very low frequency in the general population, has been reported to segregate with disease and is present in multiple individuals with hypercholesterolemia, and has been shown to affected protein function in vitro. For these reasons, it has been classified as Pathogenic.
LDLR-LOVD, British Heart Foundation RCV000211583 SCV000294591 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000211583 SCV000322886 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research 0/208 non-FH alleles; 0/100 healthy control individuals; 0/60 healthy control individuals
Robarts Research Institute,Western University RCV000211583 SCV000484724 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 RCV000211583 SCV000503127 likely pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 8 , family members = 12 with co-segregation / FH-Lancashire
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000211583 SCV000583649 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Fundacion Hipercolesterolemia Familiar RCV000211583 SCV000607441 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
GeneDx RCV000162016 SCV000617500 pathogenic not provided 2017-09-07 criteria provided, single submitter clinical testing The E101K (aka E80K, FH Lancashire) pathogenic variant is part of a negatively charged triplet, Ser-Asp-Glu, located at the carboxyl-terminal end of the LDL-receptor A2 repeat domain in the LDLR gene, and is critical for ligand binding (Schneider et al., 2003). E101K has been published numerous times in unrelated patients from different ethnic backgrounds with FH (Webb et al., 1992; Wang et al., 2001; Mozas et al., 2004; Robles-Osorio et al., 2006; Humphries et al., 2006; Al-Khateeb et al., 201; Futema et al., 2013). Patient protein studies and in vitro analysis support alteration to protein processing and intracellular transport, in the presence of E101K (Webb et al., 1992; Thormaehlen et al., 2015). E101K results in a non-conservative amino acid substitution at a position that is conserved across species. Additionally, this variant is classified as pathogenic/likely pathogenic and reported to segregate with disease by other clinical laboratories in ClinVar (ClinVar SCV000285028.2, SCV000484724.1, SCV000503127.1, SCV000583649.1, SCV000268550.1, ; Landrum et al., 2016). Furthermore, the E101K variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000844744 SCV000711395 pathogenic Familial hypercholesterolemia - homozygous 2017-10-16 criteria provided, single submitter clinical testing The p.Glu101Lys variant in LDLR has been reported in the heterozygous state in > 30 individuals with familial hypercholesterolemia (FH), in the compound heterozy gous state in 1 individual with homozygous FH (Loux 1992, Webb 1992, Garcia-Garc ia 2001, Mozas 2004, Humphries 2006, Miyakem2009, Taylor 2010, Futema 2013, Do 2 015) and segregated with disease in four affected relatives from two families (W ebb 1992, Loux 1992). This variant has also been reported by other clinical labo ratories in ClinVar (Variation ID# 161266). In vitro functional studies provide some evidence that the p.Glu101Lys variant may impact protein function (Webb 199 2). This variant has also been identified in 3/111700 European chromosomes by th e Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). This f requency is low enough to be consistent with the frequency of FH in the general population. Computational prediction tools and conservation analysis suggests th at the p.Glu101Lys variant may impact the protein. In summary, this variant meet s criteria to be classified as pathogenic for FH in an autosomal dominant manner based upon presence in multiple affected individuals, segregation studies, low frequency in the general population and computational and functional evidence. A CMG/AMP Criteria applied: PS4, PM2, PS3_Supporting, PP1_Moderate, PP3.
Iberoamerican FH Network RCV000211583 SCV000748036 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Fulgent Genetics,Fulgent Genetics RCV000211583 SCV000894165 pathogenic Familial hypercholesterolemia 1 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000775032 SCV000909129 pathogenic Familial hypercholesterolemia 2017-07-25 criteria provided, single submitter clinical testing Pathogenic variant based on current evidence: This missense variant (also known as p.Glu80Lys in the mature protein) is located in the LDLR type A repeat 2 of the ligand binding domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. Experimental studies have shown that this variant significantly inhibits LDL uptake (PMID: 25647241). This variant has been reported in more than 10 individuals affected with hypercholesterolemia (PMID: 1352322, 11668627, 23669246, 18718593, 19843101, 15241806, 20236128, 17142622, 16314194, 11668640) and reported to segregate with disease in two families (PMID: 1301940 and 1352322). This variant is rare in the general population and has been identified in 4/246246 chromosomes by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000775032 SCV000919570 pathogenic Familial hypercholesterolemia 2018-01-19 criteria provided, single submitter clinical testing Variant summary: The LDLR c.301G>A (p.Glu101Lys) variant involves the alteration of a conserved nucleotide located in the low-density lipoprotein (LDL) receptor class A repeat (InterPro) and 4/5 in silico tools predict a damaging outcome for this variant. One functional study, Thormaehlen_2015, found this variant to be associated with pronouncedly inhibited LDL-uptake in cells." This variant was found in 4/263560 control chromosomes (gnomAD and publication controls) at a frequency of 0.0000152, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). This variant was found in multiple unrelated patients with FH (Al-Khateeb_2011, Khera_2016, Futema_2013). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000162016 SCV000189619 not provided not provided no assertion provided in vitro
CSER _CC_NCGL, University of Washington RCV000148571 SCV000190284 likely pathogenic Hypercholesterolaemia 2014-06-01 no assertion criteria provided research
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211583 SCV000268550 pathogenic Familial hypercholesterolemia 1 2008-06-05 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000211583 SCV000606069 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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.