rs368657165

chr19-11107436-G-Achr19-11107436-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000527.5(LDLR):c.862G>A(p.Glu288Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,611,686 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 (★★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:22 U:1
• Conservation: PhyloP100: 9.87

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000527.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.936
• PP5: Variant 19-11107436-G-A is Pathogenic according to our data. Variant chr19-11107436-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 161268.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-11107436-G-A is described in Lovd as [Pathogenic]. Variant chr19-11107436-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.862G>A	p.Glu288Lys	missense_variant	6/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.862G>A	p.Glu288Lys	missense_variant	6/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151942 Hom.: 0 Cov.: 32

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

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

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

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:22 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:12 Uncertain:1

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, 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	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	research	Iberoamerican FH Network	Mar 01, 2016	- -
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. -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
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. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 28, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	-	- -
Likely pathogenic, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Familial hypercholesterolemia Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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. -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

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	Oct 12, 2023	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) -

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

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2023

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. -

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
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

Other links and lift over

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