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rs121908029

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1_ModeratePM1PM5PP3_StrongPP5_Very_Strong

The NM_000527.5(LDLR):c.682G>A(p.Glu228Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000055 in 1,454,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E228D) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

13
4
1

Clinical Significance

Pathogenic reviewed by expert panel P:31

Conservation

PhyloP100: 9.88
Variant links:
Genes affected
LDLR (HGNC:6547): (low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. The encoded protein is normally bound at the cell membrane, where it binds low density lipoprotein/cholesterol and is taken into the cell. Lysosomes release the cholesterol, which is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2022]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PS1
Transcript NM_000527.5 (LDLR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM1
In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000527.5
PM5
Other missense variant is known to change same aminoacid residue: Variant chr19-11105589-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.994
PP5
Variant 19-11105588-G-A is Pathogenic according to our data. Variant chr19-11105588-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3691.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-11105588-G-A is described in Lovd as [Pathogenic]. Variant chr19-11105588-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LDLRNM_000527.5 linkuse as main transcriptc.682G>A p.Glu228Lys missense_variant 4/18 ENST00000558518.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LDLRENST00000558518.6 linkuse as main transcriptc.682G>A p.Glu228Lys missense_variant 4/181 NM_000527.5 P3P01130-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000161
AC:
4
AN:
247898
Hom.:
0
AF XY:
0.00000740
AC XY:
1
AN XY:
135086
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000110
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000893
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000550
AC:
8
AN:
1454752
Hom.:
0
Cov.:
34
AF XY:
0.00000692
AC XY:
5
AN XY:
722400
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000506
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000271
Gnomad4 OTH exome
AF:
0.0000167
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.0000113

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:31
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:18
Pathogenic, criteria provided, single submitterresearchFundacion Hipercolesterolemia FamiliarMar 01, 2016- -
Pathogenic, criteria provided, single submitterclinical testingCentre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-FoixDec 16, 2016subjects mutated among 2600 FH index cases screened = 9 , family members = 3 with co-segregation / FH-Canada-3, < 2% LDLR Activity / Software predictions: Damaging -
Likely pathogenic, criteria provided, single submitterclinical testingRobarts Research Institute, Western University-- -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
Likely pathogenic, criteria provided, single submitterclinical testingMolecular Genetics Laboratory, Centre for Cardiovascular Surgery and TransplantationNov 05, 2016Disrupt SDE motif. SDE bind structural Ca2+. -
Pathogenic, no assertion criteria providedresearchLaboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum-- -
Pathogenic, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, University Medical Center UtrechtJul 28, 2017- -
Pathogenic, reviewed by expert panelcurationClinGen Familial Hypercholesterolemia Variant Curation Expert PanelApr 30, 2022NM_000527.5(LDLR):c.682G>A (p.Glu228Lys) variant is classified as pathogenic for Familial Hypercholesterolemia by applying evidence code PS3, PS4, PM1, PM2, PP1_Strong, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - PopMax MAF = 0.0001105 (0.01%) in East Asian exomes (gnomAD v2.1.1). PP3 - REVEL = 0.972. It is above 0.75. PM1 - Variant meets PM2 and is missense located in exon 4 . PS3 - Three studies contribute to PS3 attribution. One (PMID: 10978268) report a level 3 assay performed on heterozygous patient's fibroblasts with radiolabeled LDL consistent with damaging effect of the variant (50% LDLR activity). The second reports a level 2 assay perfomed on homozygous patient's fibroblasts with radiolabeled LDL consistent with damaging effect of the variant (< 2% LDLR activity).The third is permformed on Heterologous cells (COS-7). FACS, CLSM and WB results in 24% LDLR expression and 21% LDL clearance. LDLR is retained in the ER. PS4 - Variant meets PM2 and is identified in 13 index cases who fulfil SB criteria for FH (n=1 CGMC, UFGOD, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière; n=1 Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge; n=1 Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation)) or DLCN criteria for FH (n=1 Robarts Research Institute; n=9 CGMC, UFGOD, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière). PP1_Strong - Variant segregate with FH in 10 informatives meiosis (6 relatives positive LDL-C > 75th percentile and 4 relatives negative LDLC < 50th percentile) from 2 families from Laboratory of Genetics and Molecular Cardiology, University of São Paulo and in 1 relative positive for variant (LDL-C > 75th percentile) from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. PP4 - Variant meets PM2 and is identified in 13 index cases who fulfil SB criteria for FH (n=1 CGMC, UFGOD, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière; n=1 Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge; n=1 Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation)) or DLCN criteria for FH (n=1 Robarts Research Institute; n=9 CGMC, UFGOD, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière). -
Pathogenic, criteria provided, single submitterresearchIberoamerican FH NetworkMar 01, 2016- -
Pathogenic, no assertion criteria providedliterature onlyOMIMApr 01, 1990- -
Pathogenic, criteria provided, single submitterclinical testingU4M - Lille University & CHRU Lille, Université de Lille - CHRU de LilleMar 30, 2017- -
Likely pathogenic, criteria provided, single submitterresearchBrunham Lab, Centre for Heart and Lung Innovation, University of British ColumbiaJan 20, 2019- -
Pathogenic, criteria provided, single submitterresearchLaboratory of Genetics and Molecular Cardiology, University of São PauloMar 01, 2016- -
Pathogenic, criteria provided, single submitterresearchCardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo JorgeMar 01, 20160/190 non-FH alleles; 0/100 Chinese normolipidemic individuals; 0/100 healthy control individuals -
Likely pathogenic, criteria provided, single submitterliterature onlyLDLR-LOVD, British Heart FoundationMar 25, 2016- -
Pathogenic, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Pathogenic, no assertion criteria providedclinical testingCardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley HospitalJul 20, 2012- -
Pathogenic, no assertion criteria providedresearchRajaie Cardiovascular, Medical and Research Center, Iran University of Medical Sciences-- -
not provided Pathogenic:5
Pathogenic, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxFeb 02, 2023Not 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; Published functional studies suggest a damaging effect with reduced mature protein, reduced cell surface localization, and reduced ligand binding (Chang et al., 2003); Also known as Glu207Lys, FH French Canadian-3, FH Mexico; This variant is associated with the following publications: (PMID: 2318961, 28965616, 22390909, 21475731, 21722902, 9484998, 31447099, 30592178, 33111339, 31372158, 34011801, 31491741, 30755392, 34037665, 33458634, 33418990, 35339733, 35480308, 32041611, 32977124, 32331935, 30710474, 33519890, 1301956, 2088165, 15359125, 18677035, 10978268, 12837857, 23375686, 12827279) -
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicFeb 22, 2023PP1_strong, PP3, PP4, PM2_supporting, PS3, PS4 -
Likely pathogenic, criteria provided, single submitterclinical testingMolecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart InstituteJul 20, 2017- -
Pathogenic, no assertion criteria providedprovider interpretationStanford Center for Inherited Cardiovascular Disease, Stanford UniversityOct 19, 2017p.Glu228Lys (c.682G>A) in exon 4 of the LDLR gene (NM_000527.4; chr19-11216264-G-A) This variant is also reported as p.Glu207Lys in the literature. SCICD Classification: pathogenic variant based on strong case data and low frequency in unselected populations. We do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: LDLR: LDL receptors are located on the surface of the liver and play an important role in LDL recycling. Pathogenic variants in LDLR account for 80% of cases of familial hypercholesterolemia. Both missense and truncating/frameshift variants can be pathogenic. Case data (not including our patient): over 400 individuals with FH (mostly of Dutch ancestry) have this variant. · ClinVar: 12 labs § Invitae, British Heart Foundation Study, CV Research Group, Robarts Research Institute, Centre de Génétique Moléculaire et Chromosomique, Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation, U4M - Lille University & CHRU Lille,Université Lille 2 - CHRU de Lille, Laboratory of Genetics and Molecular Cardiology,University of São Paulo, Fundacion Hipercolesterolemia Familiar, Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital, Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum: at least 34 people from 9 families. · Cases in the literature: · Leitersdorf et al 1990: Reported in 3 of 130 French-Canadian patients with heterozygous FH and in 2 of 11 homozygotes. · Kusters et al 2011: Determined that this variant is a Dutch founder variant. 437 out of 10,899 patients had this variant. · Vaca et al 2011: Identified this variant in 5 out of 59 Mexican patients with FH. · Huijgen et al 2012: the purpose of this study was to analyze previously-documented variants using in silico prediction tools. · Bertolini et al 2013: This variant was identified in 31 subjects from 16 families of Italian descent. Segregation data: reported (Bertolini et al 2013) but no large families with this variant have been studied for segregation data. Functional data: Zhao and Michaely (2008): The substitution of a lysine for a glutamine at this codon destroys an important binding site. The binding affinity of a nearby residue, E208, to a VLDL molecule is reduced when substituted (E208K). Conservation data: The glutamic acid at codon 228 is completely conserved across species. Nearby pathogenic variants at this codon or neighboring codons: Per the test report, "a different missense substitution at this codon (p.Glu228Gln) has been determined to be pathogenic (PMID: 1301956, 8882879, 16250003, 17094996). This variant has not been reviewed by our team. Population data: Highest MAF in East Asian population: 0.011%. The variant was reported online in 4 of 122,190 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 2 of 8,588 individuals of East Asian descent (MAF=0.011%), 1 of 16,777 individuals of Latino descent and 1 of 55,223 individuals of European descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. -
Familial hypercholesterolemia Pathogenic:5
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Feb 04, 2021- -
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 31, 2024This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 228 of the LDLR protein (p.Glu228Lys). This variant is present in population databases (rs121908029, gnomAD 0.01%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 2318961, 21475731, 21722902, 22390909, 23375686). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Glu207Lys. ClinVar contains an entry for this variant (Variation ID: 3691). 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: 18677035). This variant disrupts the p.Glu228 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301956, 8882879, 16250003, 17094996). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthMar 22, 2019This variant (also known as p.Glu207Lys in the mature protein and as FH Canadian-3, FH Modena, and FH Mexico-3) is a missense variant located in the fifth LDLR type A repeat of the ligand binding domain of the LDLR protein that forms a calcium binding pocket. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. In experimental studies, the mutant protein has shown normal LDL binding affinity but reduced affinity for _x0001_beta-VLDL (PMID: 18677035) and delayed processing to the mature form (PMID: 2318961). This has been identified in numerous individuals diagnosed with familial hypercholesterolemia (PMID: 2318961, 15359125, 21475731, 21722902, 22390909, 23375686). This variant has been identified in 4/247898 chromosomes by the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJul 30, 2018Variant summary: LDLR c.682G>A (p.Glu228Lys) results in a conservative amino acid change located in the Low-density lipoprotein (LDL) receptor class A repeat of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 244390 control chromosomes. c.682G>A has been reported in the literature in numerous individuals affected with Familial Hypercholesterolemia. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, showing the variant to result in impaired lipoprotein binding (Hobbs_1992). In addition, other variants at this codon have been reported as pathogenic (p.Glu228Gln, p.Glu228X). 12 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitterresearchLaboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine-- -
Homozygous familial hypercholesterolemia Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJul 31, 2017The p.Glu228Lys variant in LDLR is a common pathogenic variant that has been rep orted in a large number of individuals across several studies (Kusters 2011, Huj gen 2012, Bertolini 2013, Leitersdorf 1990). It is one of the 12 most common LD LR variants in the Dutch (Kusters 2011). This variant has been identified in 2/1 7176 East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://g nomad.broadinstitute.org; dbSNP rs121908029). In vitro functional studies suppor t that the p.Glu228Lys impacts protein function (Leitersdorf 1990). In addition, several other variants at the same position (p.Glu228Gln, p.Glu228Ala, p.Glu228 Gly) have been reported with evidence supporting a disease causing role (ClinVar ID: 251393, 251394, 375796), suggesting that a change at this position is not t olerated. In summary, this variant meets criteria to be classified as pathogenic for familial hypercholesterolemia in an autosomal dominant manner based upon fu nctional studies, presence in multiple affected individuals, low frequency in co ntrols and pathogenicity of other variants at the same amino acid position. ACMG /AMP Criteria applied: PS4, PM5_Strong, PM2, PS3_Supporting. -
Stroke disorder;C0265101:Carotid artery occlusion;C0338585:Carotid artery dissection;C0340643:Aortic dissection;C0751815:Internal carotid artery dissection Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCenter for Personalized Medicine, Children's Hospital Los Angeles-- -
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsAug 17, 2022The p.E228K pathogenic mutation (also known as c.682G>A), located in coding exon 4 of the LDLR gene, results from a G to A substitution at nucleotide position 682. The glutamic acid at codon 228 is replaced by lysine, an amino acid with similar properties. This alteration, historically described as p.E207K, FH French Canadian, FH Mexico-3, and FH-Modena, has been detected in numerous individuals with familial hypercholesterolemia (FH) across multiple ethnicities (Leitersdorf E et al. J. Clin. Invest., 1990 Apr;85:1014-23; Bertolini S et al. Arterioscler. Thromb. Vasc. Biol., 2000 Sep;20:E41-52; Kim HN et al. Chonnam Med J, 2018 Jan;54:31-35). Functional studies have demonstrated decreased amounts of mature mRNA, reduced protein transport from the endoplasmic reticulum, and LDLR activity that is 40-45% of wild-type levels (Leitersdorf E et al. J. Clin. Invest., 1990 Apr;85:1014-23; Bertolini S et al. Arterioscler. Thromb. Vasc. Biol., 2000 Sep;20:E41-52; Chang JH et al. J. Lipid Res., 2003 Oct;44:1850-8). Furthermore, an alternate nucleotide change at this position, c.682G>C p.E228Q (also known as p.E207Q, FH Tulsa-2, FH Iraq) has been well-described as a mutation in numerous individuals with FH, suggesting a likely hotspot location (Hobbs HH et al. Hum. Mutat., 1992;1:445-66). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.93
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.60
Cadd
Pathogenic
30
Dann
Pathogenic
1.0
DEOGEN2
Pathogenic
0.95
D;.;.;.
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.89
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
1.0
D;D;D;D
M_CAP
Pathogenic
0.85
D
MetaRNN
Pathogenic
0.99
D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
4.4
H;.;.;H
MutationTaster
Benign
1.0
D;D;D;D;D;D;D
PrimateAI
Uncertain
0.54
T
PROVEAN
Uncertain
-3.7
D;D;D;D
Sift
Uncertain
0.0010
D;D;D;D
Sift4G
Uncertain
0.015
D;D;D;D
Polyphen
1.0
D;.;.;.
Vest4
0.84
MutPred
0.96
Gain of ubiquitination at E228 (P = 0.009);Gain of ubiquitination at E228 (P = 0.009);.;Gain of ubiquitination at E228 (P = 0.009);
MVP
1.0
MPC
0.86
ClinPred
0.99
D
GERP RS
5.6
Varity_R
0.99
gMVP
1.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121908029; hg19: chr19-11216264; COSMIC: COSV52945096; COSMIC: COSV52945096; API