rs139791325

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM1PP2BP4

The NM_000527.5(LDLR):c.1876G>A(p.Glu626Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000268 in 1,613,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:13B:2O:1

Conservation

PhyloP100: 4.79

Publications

14 publications found

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 Gene-Disease associations (from GenCC):

hypercholesterolemia, familial, 1
Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
homozygous familial hypercholesterolemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LDLR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 23 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_000527.5

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 678 curated pathogenic missense variants (we use a threshold of 10). The gene has 92 curated benign missense variants. Gene score misZ: 0.12407 (below the threshold of 3.09). Trascript score misZ: 0.59338 (below the threshold of 3.09). GenCC associations: The gene is linked to hypercholesterolemia, familial, 1, homozygous familial hypercholesterolemia.

BP4

Computational evidence support a benign effect (MetaRNN=0.33752286).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5 link	c.1876G>A	p.Glu626Lys	missense_variant	Exon 13 of 18	ENST00000558518.6	NP_000518.1	P01130-1A0A024R7D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 link	c.1876G>A	p.Glu626Lys	missense_variant	Exon 13 of 18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000314

AC:

AN:

251492

AF XY:

0.000324

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.000615

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000274

AC:

400

AN:

1461818

Hom.:

Cov.:

AF XY:

0.000263

AC XY:

191

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33474

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000153

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000300

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000312

AC:

347

AN:

1111948

Other (OTH)

AF:

0.000480

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

119

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000217

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41436

American (AMR)

AF:

0.000328

AC:

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000309

AC:

AN:

68026

Other (OTH)

AF:

0.000478

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000352

Hom.:

Bravo

AF:

0.000174

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000486

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:13Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:2Uncertain:5Benign:1

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

0/200 non-FH alleles -

Feb 19, 2019

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method: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. -

May 25, 2011

Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 27, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method: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. -

Jan 31, 2024

U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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. -

Jul 30, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance:Likely benign

Review Status:flagged submission

Collection Method:literature only

- -

not provided

Pathogenic:1Uncertain:2Other:1

Mar 25, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method: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. -

Sep 29, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP1_moderate, PS3 -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dept. of Genetics and Pharmacogenomics, Merck Research Labs

Significance:not provided

Review Status:no classification provided

Collection Method:in vitro

- -

not specified

Uncertain:3

May 04, 2022

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method: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). -

Nov 14, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method: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. -

Familial hypercholesterolemia

Uncertain:2Benign:1

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 06, 2025

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method: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 suggests that this variant may have 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. -

Sep 16, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Cardiovascular phenotype

Uncertain:1

Jun 11, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method: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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.097

BayesDel_noAF

Pathogenic

0.27

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

D;.;.;.;.;.

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.12

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.97

D;D;D;D;D;D

M_CAP

Pathogenic

0.46

MetaRNN

Benign

0.34

T;T;T;T;T;T

MetaSVM

Uncertain

0.28

MutationAssessor

Benign

1.2

L;.;.;.;.;L

PhyloP100

4.8

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.2

D;D;D;D;D;D

REVEL

Pathogenic

0.70

Sift

Benign

0.055

T;T;T;D;T;T

Sift4G

Benign

0.092

T;T;T;T;T;T

Polyphen

0.64

P;.;.;.;.;.

Vest4

0.68

MVP

1.0

MPC

0.41

ClinPred

0.11

GERP RS

4.3

Varity_R

0.60

gMVP

0.98

Mutation Taster

=40/60

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over