ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.862G>A (p.Glu288Lys) (rs368657165)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000775051 SCV000285035 likely pathogenic Familial hypercholesterolemia 2019-04-01 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 288 of the LDLR protein (p.Glu288Lys). 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 (rs368657165, ExAC 0.02%). This variant has been reported in multiple individuals affected with hypercholesterolemia (PMID: 10090484, 11810272, 11857755, 17765246, 23375686). Experimental studies have shown that this missense change reduces the protein LDL-binding capacity and decreases LDL internalization (PMID: 21990180). For these reasons, this variant has been classified as Likely Pathogenic.
LDLR-LOVD, British Heart Foundation RCV000234348 SCV000295016 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000234348 SCV000322919 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research 0/190 non-FH alleles
Robarts Research Institute,Western University RCV000234348 SCV000484703 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 RCV000234348 SCV000503246 uncertain significance Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 2 / previously described in association with FH / Software predictions: Conflicting
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000234348 SCV000583752 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Fundacion Hipercolesterolemia Familiar RCV000234348 SCV000607509 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Iberoamerican FH Network RCV000234348 SCV000748137 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000234348 SCV000839988 likely pathogenic Familial hypercholesterolemia 1 2017-08-21 criteria provided, single submitter clinical testing This c.862G>C (p.Glu288Lys) variant in the LDLR gene has been reported in multiple patients with familial hypercholesterolemia (PMID: 21990180, 26927322). Glutamate at position 288 of the LDLR protein is highly evolutionarily conserved. Functional studies have shown that this variant disrupts normal LDLR function by decreasing its internalization and ligand binding capacity (PMID: 21990180). This variant is classified as likely pathogenic.
Color RCV000775051 SCV000909150 likely pathogenic Familial hypercholesterolemia 2019-12-29 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000826170 SCV000967709 likely pathogenic Homozygous familial hypercholesterolemia 2017-08-16 criteria provided, single submitter clinical testing The p.Glu288Lys variant in LDLR has been reported in >25 individuals with famili al hypercholesterolemia and segregated with disease in 1 affected relative (Ebha rdt 1999, Fouchier 2001, Bunn 2002, Bourbon 2008, Alonso 2009, Etxebarria 2012, Bertolini 2013, ArulJothi 2016). Additionally, this variant has been identified in 6/30782 South Asian chromosomes by the Genome Aggregation Database (gnomAD, h ttp://gnomad.broadinstitute.org/; dbSNP rs368657165) and is present in ClinVar ( Variation ID: 161268). Please note that for diseases with clinical variability, reduced penetrance, or recessive inheritance, pathogenic variants may be present at a low frequency in the general population. In vitro functional studies provi de some evidence that the p.Glu288Lys variant may impact protein function (Etxeb arria 2012). However, these types of assays may not accurately represent biologi cal function. Computational prediction tools and conservation analysis do not pr ovide strong support for or against an impact to the protein. In summary, althou gh additional studies are required to fully establish its clinical significance, the p.Glu288Lys variant is likely pathogenic. ACMG/AMP Criteria applied: PS4, P M2_Supporting, PS3_Supporting
CSER _CC_NCGL, University of Washington RCV000148573 SCV000190286 likely pathogenic Hypercholesterolaemia 2014-06-01 no assertion criteria provided research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000234348 SCV000606253 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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