rs368657165

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS3_SupportingPM2PP3PP4PS4_ModeratePP1_Strong

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023783/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

8

7

4

Clinical Significance

Pathogenic reviewed by expert panel P:24U:1

Conservation

PhyloP100: 9.87

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]

LDLR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.862G>A	p.Glu288Lys	missense_variant	6/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.862G>A	p.Glu288Lys	missense_variant	6/18	1	NM_000527.5	ENSP00000454071	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

5

AN:

151942

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.0000967

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000659

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

10

AN:

251428

Hom.:

0

AF XY:

0.0000441

AC XY:

6

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000274

AC:

40

AN:

1459626

Hom.:

0

Cov.:

32

AF XY:

0.0000248

AC XY:

18

AN XY:

726116

show subpopulations

Gnomad4 AFR exome

AF:

0.000210

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.0000664

GnomAD4 genome

AF:

0.0000329

AC:

5

AN:

152060

Hom.:

0

Cov.:

32

AF XY:

0.0000404

AC XY:

3

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.0000964

Gnomad4 AMR

AF:

0.0000658

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000543

Hom.:

0

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.000227

AC:

1

ESP6500EA

AF:

0.00

AC:

0

ExAC

AF:

0.0000330

AC:

4

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:24Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:12Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 28, 2022	- -
Likely pathogenic, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	0/190 non-FH alleles -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	research	Iberoamerican FH Network	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 23, 2023	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Aug 21, 2017	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Uncertain significance, 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	Dec 16, 2016	subjects mutated among 2600 FH index cases screened = 2 / previously described in association with FH / Software predictions: Conflicting -
Pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Jun 08, 2021	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. -

Familial hypercholesterolemia

Pathogenic:5

Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 09, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 05, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Mar 12, 2020	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. It is located within the functionally important LDL-receptor class A domain where other pathogenic or likely pathogenic missense variants have been described. Functional studies have shown that this variant disrupts normal LDLR function by decreasing its internalization and ligand binding capacity (PMID: 21990180). This variant has been identified in 11/282818 (0.004%) alleles the gnomAD population database. Multiple lines of in silico algorithms predicts this change to be deleterious. This variant is classified as pathogenic. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 23, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 22, 2022	PP1_strong, PP3, PP4, PM2, PS3_supporting, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 2024	Published functional studies demonstrate a damaging effect on protein function (PMID: 34167030, 21990180); 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, 37589137, 37409534, 34363016, 32041611, 33303402, 32220565, 34456049, 35913489, 26927322, 23675242, 21990180, 11810272, 34167030) -

Homozygous familial hypercholesterolemia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 16, 2017

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 -

Hypercholesterolemia

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

LDLR-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 25, 2024

The LDLR c.862G>A variant is predicted to result in the amino acid substitution p.Glu288Lys. This variant, also described as E267K using alternate nomenclature, has been reported in multiple individuals affected with familial hypercholesterolemia (see for example, Table 1, Ebhardt et al. 1999. PubMed ID: 10090484; Table 1, Etxebarria et al. 2011. PubMed ID: 21990180; Table S3, Bertolini et al. 2013. PubMed ID: 23375686). Consistent with this, the p.Glu288Lys variant displayed reduced LDL binding capacity in vitro (Figure 3, Etxebarria et al. 2011. PubMed ID: 21990180). This variant is reported in 0.020% of alleles in individuals of South Asian descent in gnomAD and it has been interpreted as pathogenic by the ClinGen familial hypercholesterolemia expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/161268/). Based on the available evidence, we classify this variant as pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 2024

The c.862G>A (p.E288K) alteration is located in exon 6 (coding exon 6) of the LDLR gene. This alteration results from a G to A substitution at nucleotide position 862, causing the glutamic acid (E) at amino acid position 288 to be replaced by a lysine (K). Based on data from gnomAD, the A allele has an overall frequency of 0.004% (11/282818) total alleles studied. The highest observed frequency was 0.02% (6/30616) of South Asian alleles. This mutation (also known as p.E267K) has been reported in multiple cohorts of individuals with a clinical diagnosis of hypercholesterolemia (Ebhardt, 1999; Fouchier, 2001; Bunn, 2002; Bourbon, 2008; Bertolini, 2013; ArulJothi, 2016). This amino acid position is highly conserved in available vertebrate species. Functional studies showed this mutation to have significantly decreased internalization and binding capacity (Etxebarria, 2012). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Pathogenic

0.30

D

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

29

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.77

D;.;.;.;.;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.99

D

LIST_S2

Uncertain

0.91

D;D;D;D;T;D

M_CAP

Pathogenic

0.61

D

MetaRNN

Pathogenic

0.94

D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

D

MutationAssessor

Benign

1.4

L;.;.;.;.;L

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.56

T

PROVEAN

Uncertain

-3.3

D;D;D;D;D;D

REVEL

Pathogenic

0.85

Sift

Benign

0.043

D;T;T;D;D;D

Sift4G

Benign

0.070

T;T;T;T;D;T

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.87

MVP

1.0

MPC

0.86

ClinPred

0.54

D

GERP RS

5.3

Varity_R

0.83

gMVP

0.91

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: rs368657165; hg19: chr19-11218112; COSMIC: COSV52941838; COSMIC: COSV52941838;