ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.829G>A (p.Glu277Lys)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Biomarker Research Laboratory,Mayo Clinic RCV000210246 SCV000266310 likely benign Familial hypercholesterolemia 1 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.
Invitae RCV000776470 SCV000285034 benign Familial hypercholesterolemia 2020-12-04 criteria provided, single submitter clinical testing
LDLR-LOVD, British Heart Foundation RCV000210246 SCV000295006 likely benign Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000210246 SCV000322918 uncertain significance Familial hypercholesterolemia 1 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 1 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
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000210246 SCV000540898 uncertain significance Familial hypercholesterolemia 1 2017-03-20 criteria provided, single submitter clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000210246 SCV000583745 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000210246 SCV000588522 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
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 1 2016-03-01 criteria provided, single submitter research
Color Health, Inc RCV000776470 SCV000912020 benign Familial hypercholesterolemia 2018-08-27 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000610848 SCV000917586 benign not specified 2021-02-01 criteria provided, single submitter clinical testing Variant summary: LDLR c.829G>A (p.Glu277Lys) results in a conservative amino acid change located in a class A repeat (IPR002172) in 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 0.00054 in 251484 control chromosomes, predominantly within the South Asian and Southern European subpopulations at a frequency of 0.0016 and 0.0012, respectively (gnomAD). The observed variant frequency in these subpopulations is close to- or higher than the expected allele frequency for a pathogenic variant in LDLR causing Familial Hypercholesterolemia phenotype (0.0013), strongly suggesting that the variant is a benign polymorphism. c.829G>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia, but also in controls (e.g. Ekstrom_1995, Pereira_1995, Descamps_1997, Ekstrom_2000, Weiss_2000, Fouchier_2001, Bertolini_2000, Mozas_2004. Ejarque_2008). Of note, in many of these patients co-occurrences with other pathogenic variants in cis have been reported (e.g. c.12G>A (p.Trp4X), c.460C>T (p.Gln154X), c.1326C>G (p.Tyr442X), c.2393_2401del9; see e.g. in Mozas_2004), providing supporting evidence for a benign role. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated normal expression level, and LDL uptake for the variant protein (e.g. Ekstrom_2000, Thormaehlen_2015, RodriguezJimenez_2019). 13 other 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. Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000161968 SCV001134270 likely benign not provided 2019-03-25 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000210246 SCV001285929 likely benign Familial hypercholesterolemia 1 2018-03-12 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Laboratory of Molecular Genetics,National Medical Research Center for Therapy and Preventive Medicine RCV000776470 SCV001482458 uncertain significance Familial hypercholesterolemia criteria provided, single submitter research
Nilou-Genome Lab RCV000210246 SCV001653437 uncertain significance Familial hypercholesterolemia 1 2021-05-18 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
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000210246 SCV000606243 benign Familial hypercholesterolemia 1 no assertion criteria provided research
Clinical Genetics,Academic Medical Center RCV000610848 SCV001918264 benign not specified no assertion criteria provided clinical testing

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