Submissions for variant NM_000527.5(LDLR):c.1876G>A (p.Glu626Lys)

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000211563	SCV000296926	uncertain significance	Hypercholesterolemia, familial, 1	2015-07-30	criteria provided, single submitter	clinical testing
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000211563	SCV000322984	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research	0/200 non-FH alleles
Laboratory for Molecular Medicine, Mass General Brigham 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).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000771317	SCV000544656	likely benign	Familial hypercholesterolemia	2025-01-19	criteria provided, single submitter	clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000211563	SCV000583902	pathogenic	Hypercholesterolemia, familial, 1	2024-01-31	criteria provided, single submitter	clinical testing	This missense variant LDLR:c.1876G>A (also known as p.Glu605Lys in the mature protein), replaces a glutamic acid with lysine at codon 626 of the LDLR protein (p.Glu626Lys). According to updated genomic data and to ClinGen FH VCEP criteria issued in 2022 (PMID: 34906454) for the validation of pathogenicity of LDLR variants, this variant may now be classified as “Pathogenic" with low penetrance from evidence as follows. It is located within a highly conserved motif of a functional domain (LDLR Class B6) essential for LDL binding and LDLR recycling to the plasma membrane. Despite being previously classified as VUS according to standard ACMG criteria and found as VUS in multiple records in ClinVar, recent in-vitro studies (PMID: 35568682) have reclassified this variant as “Pathogenic” based on level 1 functional tests showing significantly reduced LDL binding and internalization (PS3-strong) and cosegregation found with FH in at least 6 informative meioses (PP1-Strong). In addition, this variant was observed in the context of genetic testing in a patient exhibiting a phenotype (Dutch Lipid Clinic Network Scoring=11) of definite FH (PP4), and is now borderline to meeting criteria PM2 (GnomAD= 0.000217 (<0.0002) and no homozygotes) and PP3 (REVEL Score= 0,71, ≥0,75). Studies mentioning this variant as likely benign performed as part of screening studies before 2013, and discordant observations suggesting VUS in previous CLinGen reports, are in favor of a lowered penetrance for this variant.
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000211563	SCV000588620	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV000771317	SCV000903575	uncertain significance	Familial hypercholesterolemia	2023-12-07	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 626 of the LDLR protein. This variant is also known as p.Glu605Lys in the mature protein. This variant alters a conserved glutamic acid residue in the LDLR type B repeat 6 of the LDLR protein (a.a. 616-658), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. Functional studies have shown that this variant causes a decrease in LDLR internalization, uptake and activity (PMID: 35568682, 37719435); a different high-throughput cell-based assay was inconclusive regarding the impact of this variant on the LDLR function (PMID: 25647241). This variant has been reported in several individuals affected with familial hypercholesterolemia (PMID: 16250003, 20828696, 27596133, 35474963, 37848354). Two of these individuals also carried a different pathogenic LDLR missense variant (PMID: 27596133). In a large myocardial infarction case-control study conducted in Europe and North America, this variant was reported in 4/3726 cases and 3/3668 controls, showing inconclusive association with disease (PMID: 25487149). This variant has been identified in 83/282896 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000454999	SCV000919576	uncertain significance	not specified	2022-11-14	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1876G>A (p.Glu626Lys) results in a conservative amino acid change 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 0.00032 in 253384 control chromosomes (gnomAD and Do_2015), predominantly at a frequency of 0.00062 within the Non-Finnish European subpopulation in the gnomAD database. 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. c.1876G>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia and has been reported to segregate within disease, however it has also been reported in the compound heterozygous state in individuals with a pathogenic variant (e.g. Fouchier_2005, Medeiros_2014, Thormaehlen_2015, Benito-Vicente_2015, Do_2015, Grenkowitz_2016,Futema_2021, Graca_2022). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. At least two publications report experimental evidence evaluating an impact on protein function, however the results indicate the effect is unclear (e.g. Thormaehlen_2015, Graca_2022). The variant was found to have normal expression and ligand binding levels, but showed reduced cellular internalization, approximately 60% of the WT protein, suggesting it may impact function (Graca_2022). Eleven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. The majority classified the variant as VUS (n=9), one classified it as likely pathogenic, and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Illumina Laboratory Services, Illumina	RCV000211563	SCV001283054	uncertain significance	Hypercholesterolemia, familial, 1	2019-02-19	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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Mendelics	RCV000454999	SCV002518184	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002408721	SCV002721109	uncertain significance	Cardiovascular phenotype	2024-06-11	criteria provided, single submitter	clinical testing	The p.E626K variant (also known as c.1876G>A), located in coding exon 13 of the LDLR gene, results from a G to A substitution at nucleotide position 1876. The glutamic acid at codon 626 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in familial hypercholesterolemia (FH) cohorts; however, clinical details were limited (Fouchier SW et al. Hum Mutat, 2005 Dec;26:550-6; Medeiros AM et al. Atherosclerosis, 2010 Oct;212:553-8; Liu DJ et al. Nat Genet, 2014 Feb;46:200-4; Benito-Vicente A et al. Genet Med, 2015 Dec;17:980-8; Taylor JC et al. Nat Genet, 2015 Jul;47:717-726; Thormaehlen AS et al. PLoS Genet, 2015 Feb;11:e1004855; Grenkowitz T et al. Atherosclerosis, 2016 10;253:88-93; Besseling J et al. Eur Heart J, 2017 Feb;38:565-573; Benedek P et al. J Intern Med, 2018 12;284:674-684). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
All of Us Research Program, National Institutes of Health	RCV000211563	SCV004818461	uncertain significance	Hypercholesterolemia, familial, 1	2024-09-27	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 626 of the LDLR protein. This variant is also known as p.Glu605Lys in the mature protein. This variant alters a conserved glutamic acid residue in the LDLR type B repeat 6 of the LDLR protein (a.a. 616-658), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. Functional studies have shown that this variant causes a decrease in LDLR internalization, uptake and activity (PMID: 35568682, 37719435); a different high-throughput cell-based assay was inconclusive regarding the impact of this variant on the LDLR function (PMID: 25647241). This variant has been reported in several individuals affected with familial hypercholesterolemia (PMID: 16250003, 20828696, 27596133, 35474963, 37848354). Two of these individuals also carried a different pathogenic LDLR missense variant (PMID: 27596133). In a large myocardial infarction case-control study conducted in Europe and North America, this variant was reported in 4/3726 cases and 3/3668 controls, showing inconclusive association with disease (PMID: 25487149). This variant has been identified in 83/282896 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000162004	SCV005198660	uncertain significance	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000162004	SCV005413319	likely pathogenic	not provided	2023-09-29	criteria provided, single submitter	clinical testing	PP1_moderate, PS3
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000162004	SCV005625826	uncertain significance	not provided	2024-03-25	criteria provided, single submitter	clinical testing	The LDLR c.1876G>A (p.Glu626Lys) variant has been reported in the published literature in individuals with familial hypercholesterolemia (FH) and dyslipidemia, with or without cardiac involvement (PMIDs: 37848354 (2023), 35913489 (2022), 27417002 (2016), 25741862 (2015), 24507775 (2014), 20828696 (2010), 16250003 (2005)). This variant has been shown to be associated with disease in 3 Portuguese families with childhood hypercholesterolemia (PMID: 24627126 (2014)). However, it has also been seen with additional pathogenic LDLR variants in individuals with FH, suggesting this variant may not be the cause of disease (PMID: 27596133 (2016)). Functional studies report a partial reduction in LDLR activity, such as LDL binding and lipid mobilization, however it is unclear if this impact is pathogenic (PMIDs: 37719435 (2023), 35568682 (2022), 35474963 (2022), 25647241 (2015)). The frequency of this variant in the general population, 0.0018 (47/26134 chromosomes in Swedish subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs	RCV000162004	SCV000189579	not provided	not provided		no assertion provided	in vitro
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211563	SCV000268644	pathogenic	Hypercholesterolemia, familial, 1	2011-05-25	no assertion criteria provided	clinical testing
LDLR-LOVD, British Heart Foundation	RCV000211563	SCV000295735	likely benign	Hypercholesterolemia, familial, 1	2016-03-25	flagged submission	literature only
Natera, Inc.	RCV000771317	SCV001461322	uncertain significance	Familial hypercholesterolemia	2020-09-16	no assertion criteria provided	clinical testing