Submissions for variant NM_000527.5(LDLR):c.862G>A (p.Glu288Lys)

gnomAD frequency: 0.00003  dbSNP: rs368657165

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000234348	SCV001960915	pathogenic	Hypercholesterolemia, familial, 1	2021-06-08	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.862G>A (p.Glu288Lys) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PP1_Strong, PM2, PS4_Moderate, PP3, PP4 and PS3_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PP1_strong - variant segregates with FH phenotype in 13 informative meiosis in at least 6 families from different labs. PM2 - PopMax MAF = 0.0001960 (0.0196%) in South Asian exomes (gnomAD v2.1.1). PS4_moderate - Variant meets PM2. Variant identified in at least 7 unrelated index cases with Simon-Broome criteria for FH from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge. PP3 - REVEL = 0.85. PP4 - Variant meets PM2. Identified in 7 unrelated index cases who fulfill Simon-Broome criteria for FH from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. PS3_supporting - Level 3 assays: PMID 21990180: Htz Patient lymphocytes, FACS assays - results - normal (90%) cell surface LDLR, 50% LDL-LDLR binding and 45% LDL uptake ---- results are below 85% of wild-type activity, so PS3_supporting is Met.
Invitae	RCV000775051	SCV000285035	pathogenic	Familial hypercholesterolemia	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 288 of the LDLR protein (p.Glu288Lys). This variant is present in population databases (rs368657165, gnomAD 0.02%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 10090484, 11810272, 11857755, 17765246, 23375686). ClinVar contains an entry for this variant (Variation ID: 161268). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects LDLR function (PMID: 21990180). For these reasons, this variant has been classified as Pathogenic.
LDLR-LOVD, British Heart Foundation	RCV000234348	SCV000295016	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000234348	SCV000322919	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research	0/190 non-FH alleles
Robarts Research Institute, Western University	RCV000234348	SCV000484703	likely pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000234348	SCV000503246	uncertain significance	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 2 / previously described in association with FH / Software predictions: Conflicting
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000234348	SCV000583752	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Fundacion Hipercolesterolemia Familiar	RCV000234348	SCV000607509	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Iberoamerican FH Network	RCV000234348	SCV000748137	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000234348	SCV000839988	likely pathogenic	Hypercholesterolemia, familial, 1	2017-08-21	criteria provided, single submitter	clinical testing	This c.862G>C (p.Glu288Lys) variant in the LDLR gene has been reported in multiple patients with familial hypercholesterolemia (PMID: 21990180, 26927322). Glutamate at position 288 of the LDLR protein is highly evolutionarily conserved. Functional studies have shown that this variant disrupts normal LDLR function by decreasing its internalization and ligand binding capacity (PMID: 21990180). This variant is classified as likely pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000775051	SCV000909150	pathogenic	Familial hypercholesterolemia	2023-01-09	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 288 in the seventh LDLR type A repeat of the ligand binding domain of the LDLR protein. This variant is also known as p.Glu267Lys in the mature protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has demonstrated that the variant causes a partial loss of LDL binding and internalization function of LDLR protein compared to wild-type (PMID: 21990180). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 10090484, 11810272, 11857755, 17765246, 19318025, 21990180, 23375686, 26927322, 30016271, 32041611, 33508743, communication with an external laboratory; ClinVar SCV000322919.1, SCV000484703.1). It has been shown that this variant segregates with disease in multiple individuals from six families (communication with an external laboratory; ClinVar SCV000322919.1, SCV000484703.1). This variant has also been observed in compound heterozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 35052492; ClinVar SCV000484703.1). This variant has been identified in 11/282818 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000826170	SCV000967709	likely pathogenic	Homozygous familial hypercholesterolemia	2017-08-16	criteria provided, single submitter	clinical testing	The p.Glu288Lys variant in LDLR has been reported in >25 individuals with famili al hypercholesterolemia and segregated with disease in 1 affected relative (Ebha rdt 1999, Fouchier 2001, Bunn 2002, Bourbon 2008, Alonso 2009, Etxebarria 2012, Bertolini 2013, ArulJothi 2016). Additionally, this variant has been identified in 6/30782 South Asian chromosomes by the Genome Aggregation Database (gnomAD, h ttp://gnomad.broadinstitute.org/; dbSNP rs368657165) and is present in ClinVar ( Variation ID: 161268). Please note that for diseases with clinical variability, reduced penetrance, or recessive inheritance, pathogenic variants may be present at a low frequency in the general population. In vitro functional studies provi de some evidence that the p.Glu288Lys variant may impact protein function (Etxeb arria 2012). However, these types of assays may not accurately represent biologi cal function. Computational prediction tools and conservation analysis do not pr ovide strong support for or against an impact to the protein. In summary, althou gh additional studies are required to fully establish its clinical significance, the p.Glu288Lys variant is likely pathogenic. ACMG/AMP Criteria applied: PS4, P M2_Supporting, PS3_Supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000775051	SCV001572401	pathogenic	Familial hypercholesterolemia	2021-04-05	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.862G>A (p.Glu288Lys) results in a conservative amino acid change located in the ligand binding domain (Etxebarria_2012) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251428 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (4e-05 vs 0.0013), allowing no conclusion about variant significance. c.862G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Ebhardt_1999, Etxebarria_2012, Bertolini_2013, Futema_2021). These data indicate that the variant is very likely to be associated with disease. At least one functional study reports experimental evidence evaluating an impact on protein function and results in diminished binding activity (Etxebarria_2012). 11 ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1), pathogenic (n=2) and likely pathogenic (n=8). Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000234348	SCV002022662	pathogenic	Hypercholesterolemia, familial, 1	2022-07-28	criteria provided, single submitter	clinical testing
GeneDx	RCV001843483	SCV002102632	pathogenic	not provided	2023-10-12	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on protein function (Etxebarria et al., 2012; Alves et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.E267K; This variant is associated with the following publications: (PMID: 19318025, 29874871, 34037665, 33418990, 30016271, 32660911, 35052492, 32719484, 31447099, 23375686, 25637381, 11857755, 15556094, 10090484, 17765246, 27765764, 21990180, 32041611, 33303402, 32220565, 34456049, 35913489, 26927322, 23675242, 11810272, 34167030)
Mendelics	RCV000234348	SCV002516649	pathogenic	Hypercholesterolemia, familial, 1	2022-05-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002371991	SCV002687781	pathogenic	Cardiovascular phenotype	2023-07-13	criteria provided, single submitter	clinical testing	The p.E288K pathogenic mutation (also known as c.862G>A), located in coding exon 6 of the LDLR gene, results from a G to A substitution at nucleotide position 862. The glutamic acid at codon 288 is replaced by lysine, an amino acid with similar properties. This mutation (also known as p.E267K) has been reported in multiple cohorts of patients with a clinical diagnosis of hypercholesterolemia (Ebhardt M et al. Hum. Mutat., 1999;13:257; Bunn CF et al. Hum. Mutat., 2002 Mar;19:311; Bourbon M et al. Atherosclerosis, 2008 Feb;196:633-42; Fouchier SW et al. Hum. Genet., 2001 Dec;109:602-15; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; ArulJothi KN et al. Clin. Biochem., 2016 Jun;49:669-674). Functional studies showed this mutation to have significantly decreased internalization and binding capacity (Etxebarria A et al. Hum. Mutat., 2012 Jan;33:232-43). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001843483	SCV004220001	pathogenic	not provided	2022-11-23	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0002 (6/30616 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in patients affected with familial hypercholesterolemia (PMIDs: 35052492 (2022), 30016271 (2018), 26927322 (2016), 23375686 (2013), 19318025 (2009), 17765246 (2008)). A functional study indicate that this variant impacts protein function (PMID: 21990180 (2012)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV001843483	SCV004227677	pathogenic	not provided	2022-03-22	criteria provided, single submitter	clinical testing	PP1_strong, PP3, PP4, PM2, PS3_supporting, PS4_moderate
All of Us Research Program, National Institutes of Health	RCV000234348	SCV004820227	pathogenic	Hypercholesterolemia, familial, 1	2023-10-23	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 288 in the seventh LDLR type A repeat of the ligand binding domain of the LDLR protein. This variant is also known as p.Glu267Lys in the mature protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has demonstrated that the variant causes a partial loss of LDL binding and internalization function of LDLR protein compared to wild-type (PMID: 21990180). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 10090484, 11810272, 11857755, 17765246, 19318025, 21990180, 23375686, 26927322, 30016271, 32041611, 33508743, communication with an external laboratory; ClinVar SCV000322919.1, SCV000484703.1). It has been shown that this variant segregates with disease in multiple individuals from six families (communication with an external laboratory; ClinVar SCV000322919.1, SCV000484703.1). This variant has also been observed in compound heterozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 35052492; ClinVar SCV000484703.1). This variant has been identified in 11/282818 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
CSER _CC_NCGL, University of Washington	RCV002051661	SCV000190286	likely pathogenic	Hypercholesterolemia	2014-06-01	no assertion criteria provided	research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000234348	SCV000606253	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Natera, Inc.	RCV000775051	SCV001460259	likely pathogenic	Familial hypercholesterolemia	2020-09-16	no assertion criteria provided	clinical testing