ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.829G>A (p.Glu277Lys) (rs148698650)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 14
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Biomarker Research Laboratory,Mayo Clinic RCV000210246 SCV000266310 likely benign Familial hypercholesterolemia 2015-08-31 criteria provided, single submitter research MAF =<0.3%, likely pathogenic based on the integrative in-silico score. "Little/No effect" on the LDL receptor activity based on experimental validation.
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000210246 SCV000322918 uncertain significance Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research 0/190 non-FH alleles; 0/60 healthy control individuals
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000210246 SCV000503243 benign Familial hypercholesterolemia 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 15 , family members = 5 / for 14 index cases among 15 this variant is associated with c.1268T>C, p.Ile423Thr that seems to be more deleterious / Software predictions: Conflicting
Color RCV000776470 SCV000912020 benign Familial hypercholesterolemias 2018-08-27 criteria provided, single submitter clinical testing
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000161968 SCV000189543 not provided not provided no assertion provided in vitro
GeneDx RCV000610848 SCV000730507 likely benign not specified 2017-12-29 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Iberoamerican FH Network RCV000210246 SCV000748041 uncertain significance Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV000610848 SCV000917586 likely benign not specified 2018-09-04 criteria provided, single submitter clinical testing Variant summary: LDLR c.829G>A (p.Glu277Lys) results in a conservative amino acid change located in the Low-density lipoprotein (LDL) receptor class A repeat (IPR002172) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00051 in 277282 control chromosomes, predominantly within the South Asian subpopulation at a frequency of 0.0016 in the gnomAD database. This frequency within South Asian control individuals is approximately 1.3-fold above the estimated maximal expected allele frequency for a pathogenic variant in LDLR causing Familial Hypercholesterolemia phenotype (0.0013), suggesting that the variant might be a benign polymorphism found primarily in populations of South Asian origin. The variant, c.829G>A, has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia but also in controls (Pereira_1995, Descamps_1997, Weiss_2000, Fouchier_2001, Bertolini_2000, Ejarque_2008) and co-occurring in cis with other pathogenic variants (p.I423T and p.W4X)(Ekstrom_1995, Mozas_2000). Of note, the co-occurrence of this variant in cis with W4X would be predicted to be inconsequential on the protein level, since the protein would be truncated at a point N-terminal to the region encoded by the variant. At least two publications report experimental evidence showing normal LDL uptake (Ekstrom_2000, Thormaehlen_2015). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS x4, likely benign x3, benign x2, and pathogenic x1). Based on the evidence outlined above, the variant was classified as likely benign.
Invitae RCV000210246 SCV000285034 benign Familial hypercholesterolemia 2017-04-24 criteria provided, single submitter clinical testing
LDLR-LOVD, British Heart Foundation RCV000210246 SCV000295006 likely benign Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000210246 SCV000606243 benign Familial hypercholesterolemia no assertion criteria provided research
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000210246 SCV000588522 uncertain significance Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000210246 SCV000540898 uncertain significance Familial hypercholesterolemia 2017-03-20 criteria provided, single submitter clinical testing
U4M - Lille University & CHRU Lille,Université Lille 2 - CHRU de Lille RCV000210246 SCV000583745 pathogenic Familial hypercholesterolemia 2017-03-30 criteria provided, single submitter clinical testing

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.