ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.2231G>A (p.Arg744Gln) (rs137853963)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Biomarker Research Laboratory,Mayo Clinic RCV000172965 SCV000266322 likely benign Familial hypercholesterolemia 2016-08-31 criteria provided, single submitter research MAF =<0.3%.
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000172965 SCV000503475 benign Familial hypercholesterolemia 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 7 / previously described in association with FH/Software predictions: Benign
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000058922 SCV000189587 not provided not provided no assertion provided in vitro
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000172965 SCV000296928 likely benign Familial hypercholesterolemia 2015-07-30 criteria provided, single submitter clinical testing
Institute for Integrative and Experimental Genomics,University of Luebeck RCV000172965 SCV000212142 likely pathogenic Familial hypercholesterolemia criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV000058922 SCV000697223 likely benign not provided 2017-06-01 criteria provided, single submitter clinical testing Variant summary: The LDLR c.2231G>A (p.Arg744Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is located outside of any known functional domain or repeat. 4/4 in silico tools predict benign outcome for this variant (SNP&GO was not used due to a low reliability index), however no experimental studies were published at the time of evaluation (ACMG BP4). The variant of interest has been identified in a large, broad control datasets of ExAC at a frequency of 0.0008 (99/121250 chrs tested), reaching the 0.0011 in several sub-populations (South Asians and European NF) including 1 homozygote. Although the observed frequency is similar to the estimated maximal expected allele frequency of a pathogenic LDLR variant (~0.001), thus supporting benign interpretation, the information on lipid profiling in these individuals is not available for individual review. The variant of interest was reported in multiple patients with elevated cholesterol level, including patient(s) carrying a known pathogenic variant APOB p.R3500Q (ACMG BP5), in whom lipid profiling results were not significantly different from data observed in patients carrying APOB R3500Q alone (Brusgaard, 2006) (ACMG BP5). In addition, per Dutch FH-database, cholesterol levels of R723Q positive and R723Q negative relatives are virtually similar (ACMG BS4), again favoring benign classification. The c.2231G>A was identified heterozygously in a healthy Caucasian adult undergoing carrier screening (ACMG BS2). Lastly, multiple clinical diagnostic laboratories/reputable databases classified this variant as Benign/Likely Benign (ACMG BP6). Considering all evidence the variant was conservatively classified as Likely Benign until additional evidence supporting its presence in normolipedimic control subjects is obtained.ACMG Classification: BRationale for Pathogenicity: none. Rationale for being Benign: BS2, BS4, BP4, BP5; BP6 was not engaged due to discordant classifications.
Invitae RCV000172965 SCV000627030 likely benign Familial hypercholesterolemia 2017-12-26 criteria provided, single submitter clinical testing
LDLR-LOVD, British Heart Foundation RCV000172965 SCV000295924 likely benign Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000172965 SCV000606616 benign Familial hypercholesterolemia no assertion criteria provided research
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000172965 SCV000588644 uncertain significance Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000172965 SCV000540903 likely benign Familial hypercholesterolemia 2017-03-23 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000058922 SCV000888165 benign not provided 2018-06-01 criteria provided, single submitter clinical testing
SNPedia RCV000058922 SCV000090443 not provided not provided no assertion provided not provided
U4M - Lille University & CHRU Lille,Université Lille 2 - CHRU de Lille RCV000172965 SCV000583935 likely benign Familial hypercholesterolemia 2017-03-30 criteria provided, single submitter clinical testing

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