ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1876G>A (p.Glu626Lys) (rs139791325)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211563 SCV000268644 pathogenic Familial hypercholesterolemia 2011-05-25 no assertion criteria provided clinical testing
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000211563 SCV000322984 uncertain significance Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research 0/200 non-FH alleles
Color RCV000771317 SCV000903575 uncertain significance Familial hypercholesterolemias 2018-04-20 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant (also known as p.Glu626Lys in the mature protein) is a missense variant located in the sixth LDLR type B repeat of the EGF precursor homology domain of the LDLR protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. High-throughput cell-based assay was inconclusive regarding the impact of this variant on the LDLR function (PMID 25647241). This variant been reported in several individuals affected with familial hypercholesterolemia (PMID: 16250003, 20828696, 27596133). Two of these patients also carried a deleterious LDLR missense variant (PMID 27596133). This variant has also been identified in 76/126732 chromosomes in the general non-Finnish European population by the Genome Aggregation Database (gnomAD). In a large case-control study, this variant did not show significant association with myocardial infarction (PMID 25487149). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000162004 SCV000189579 not provided not provided no assertion provided in vitro
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000211563 SCV000296926 uncertain significance Familial hypercholesterolemia 2015-07-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000454999 SCV000919576 uncertain significance not specified 2018-07-09 criteria provided, single submitter clinical testing Variant summary: LDLR c.1876G>A (p.Glu626Lys) results in a conservative amino acid change located in the LDLR class B repeat of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was observed with an allele frequency of 0.00032 in 279138 control chromosomes (gnomAD and publication). This frequency is not significantly higher than expected for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (0.00032 vs 0.0013), allowing no conclusion about variant significance. The variant, c.1876G>A, has been reported in the literature in individuals affected with Familial Hypercholesterolemia (Benito-Vicente_2015, Do_2015, Fouchier_2005, Grenkowitz_2016, Medeiros_2014, Thormaehlen_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. Two publications, one only being an abstract (Alves_2018) indicate the effects of this variant are unclear. Seven ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant with conflicting classifications, predominantly as uncertain significance (5x), 1 - likely benign, and 1 - likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000211563 SCV000544656 uncertain significance Familial hypercholesterolemia 2017-09-27 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 626 of the LDLR protein (p.Glu626Lys). 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 (rs139791325, ExAC 0.08%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with hypercholesterolemia and myocardial infarction (PMID: 16250003, 20828696, 25487149, 25647241). ClinVar contains an entry for this variant (Variation ID: 183127). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
LDLR-LOVD, British Heart Foundation RCV000211563 SCV000295735 likely benign Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000454999 SCV000539513 uncertain significance not specified 2017-02-03 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is present in HGMD in 3 papers but in cases and controls. It is classified in ClinVar with 1 star as Likely benign by British Heart Foundation, VUS by CHOP and Instituto Nacional de Saude Doutor Ricardo Jorge and Pathogenic by PathWest Laboratory Medicine WA - Fiona Stanley Hospital (in 2011). It has a max MAF in ExAC of 0.08% (56 alleles) and in gnomAD of 0.06% (75 alleles).
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000211563 SCV000588620 uncertain significance Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000211563 SCV000583902 likely pathogenic Familial hypercholesterolemia 2017-03-30 criteria provided, single submitter clinical testing

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