rs769383881

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS4_ModeratePP1_StrongPM1PM3PM2PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.337G>A (p.Glu113Lys) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PP1_Strong, PM1, PM2, PM3, PS4_Moderate and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows:PM2: PopMax MAF = 0.0001 (0.01%) in South Asian (gnomAD v4.0.0). PM1: Variant meets PM2 and is missense in exon 4.PS4_Moderate, PP4: Variant meets PM2 and is identified in at least 8 unrelated index cases who fulfill criteria for FH (1 case with possible FH by Simon Broome criteria from the Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic; 1 case with possible FH by Simon Broome criteria and 1 case with DLCN score >=6 from Service de Biochimie de Biologie Moléculaire, Hospices Civils de Lyon, France; 1 case with possible FH by Simon Broome criteria from PMID 17539906 (Taylor et al., 2007), UK; 1 case with DLCN score >=6 from PMID 16250003 (Fouchier et al., 2005), The Netherlands; 1 case with possible FH by Simon Broome criteria from PMID 10807540 (Wu et al., 2000), USA; 2 cases with definite FH by Simon Broome criteria from PMID 34456049 (Marco-Benedi et al., 2022). PP1_Strong: Variant segregates with FH phenotype in 8 informative meioses in 1 family in PMID:10807540 (Wu et al., 2000), USA: 7 affected family members have the variant.PM3: Variant meets PM2 and is identified in an index case with a homozygous FH phenotype (10 yo with LDLc= 14.9 mmol/L); variant is in compound heterozygosity with c.2389G>T (p.Val797Leu), which is classified as Likely pathogenic by these guidelines and is in trans, from Service de Biochimie de Biologie Moléculaire, Hospices Civils de Lyon, France (VCI). LINK:https://erepo.genome.network/evrepo/ui/classification/CA043209/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:16U:3

Conservation

PhyloP100: 2.65

Publications

7 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: Pathogenic. The variant received 13 ACMG points.

PS4

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

PM1

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

PM2

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

PM3

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

PP1

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 rank	MANE	Protein	UniProt
LDLR	NM_000527.5 link	c.337G>A	p.Glu113Lys	missense_variant	Exon 4 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.337G>A	p.Glu113Lys	missense_variant	Exon 4 of 18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

GnomAD2 exomes

AF:

0.0000279

AC:

AN:

250568

AF XY:

0.0000368

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000383

AC:

AN:

1461178

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

726918

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000139

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52722

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000369

AC:

AN:

1112004

Other (OTH)

AF:

0.0000166

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

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:

0.0000131

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74340

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000482

AC:

AN:

41454

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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:

0.0000328

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16Uncertain:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:7Uncertain:1

Feb 23, 2024

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000527.5(LDLR):c.337G>A (p.Glu113Lys) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PP1_Strong, PM1, PM2, PM3, PS4_Moderate and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows: PM2: PopMax MAF = 0.0001 (0.01%) in South Asian (gnomAD v4.0.0). PM1: Variant meets PM2 and is missense in exon 4. PS4_Moderate, PP4: Variant meets PM2 and is identified in at least 8 unrelated index cases who fulfill criteria for FH (1 case with possible FH by Simon Broome criteria from the Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic; 1 case with possible FH by Simon Broome criteria and 1 case with DLCN score >=6 from Service de Biochimie de Biologie Moléculaire, Hospices Civils de Lyon, France; 1 case with possible FH by Simon Broome criteria from PMID 17539906 (Taylor et al., 2007), UK; 1 case with DLCN score >=6 from PMID 16250003 (Fouchier et al., 2005), The Netherlands; 1 case with possible FH by Simon Broome criteria from PMID 10807540 (Wu et al., 2000), USA; 2 cases with definite FH by Simon Broome criteria from PMID 34456049 (Marco-Benedi et al., 2022). PP1_Strong: Variant segregates with FH phenotype in 8 informative meioses in 1 family in PMID: 10807540 (Wu et al., 2000), USA: 7 affected family members have the variant. PM3: Variant meets PM2 and is identified in an index case with a homozygous FH phenotype (10 yo with LDLc= 14.9 mmol/L); variant is in compound heterozygosity with c.2389G>T (p.Val797Leu), which is classified as Likely pathogenic by these guidelines and is in trans, from Service de Biochimie de Biologie Moléculaire, Hospices Civils de Lyon, France (VCI). -

Sep 03, 2024

All of Us Research Program, National Institutes of Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant (also known as p.Glu92Lys in the mature protein) replaces glutamic acid with lysine at codon 113 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypercholesterolemia (PMID: 16250003, 17539906). It has been shown that this variant segregates with disease in 1 family (PMID: 10807540). This variant has been identified in 8/281964 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Jun 29, 2021

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 07, 2023

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2016

Fundacion Hipercolesterolemia Familiar

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:literature only

- -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2_Supporting+PS4_Moderate+PP1_Strong -

Familial hypercholesterolemia

Pathogenic:4Uncertain:1

Oct 15, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces glutamic acid with lysine at codon 113 of the LDLR protein. This variant is also known as p.Glu92Lys in the mature protein. This variant alters a conserved AA1 residue in the LDLR type A repeat 3 of the LDLR protein (a.a. 107-145), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple unrelated individuals affected with familial hypercholesterolemia (PMID: 16250003, 17539906, 34037665, 36299643; ClinVar SCV000294636.2; SCV001950089.1, SCV000285029.6; Color internal data). It has been shown that this variant segregates with disease in eight affected individuals in one family (PMID: 10807540). This variant has been identified in 8/281964 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Jul 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 113 of the LDLR protein (p.Glu113Lys). This variant is present in population databases (rs769383881, gnomAD 0.01%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 10807540). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 237872). 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%. For these reasons, this variant has been classified as Pathogenic. -

Oct 09, 2020

Natera, Inc.

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

The p.Glu113Lys variant in LDLR has been reported in10 individuals with familial hypercholesterolemia, segregated with disease in 8 affected relatives from 1 family (PMID: 16250003, 17539906, 10807540), and has been identified in 0.01% (3/30614) of South Asian chromosomes, 0.006% (2/35432) Latino chromosomes, and 0.002% (3/128566) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs769383881). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported in ClinVar as a VUS, likely pathogenic, and pathogenic (Variation ID#: 237872). Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Glu113Lys variant is uncertain. ACMG/AMP Criteria applied: PP1_strong, BP4, PS4_supporting (Richards 2015). -

Dec 04, 2023

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: LDLR c.337G>A (p.Glu113Lys) results in a conservative amino acid change located in an LDL-receptor class A repeat (IPR002172) of 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 2.8e-05 in 250568 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.337G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (e.g., Wu_2000, Fouchier_2005, Taylor_2007, Trinder_2020, Marco-Benedi_2022, Sturm_2021), and the variant was also shown to segregate with disease in at least one family (e.g., Wu_2000). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 16250003, 34456049, 34037665, 17539906, 33079599, 10807540). Multiple submitters have reported clinical-significance assessments for this variant to ClinVar after 2014 with conflicting interpretations (pathogenic, n = 3; likely pathogenic, n = 11; VUS, n = 3). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:4

Mar 23, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The frequency of this variant in the general population, 0.000098 (3/30614 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with possible familial hypercholesterolemia (PMIDs: 34037665 (2021), 17539906 (2007)), heterozygous FH (heFH) (PMID: 34456049 (2022)), and autosomal dominant hypercholesterolemia (ADH) (PMID: 16250003 (2005)). This variant was also reported in a family with several individuals affected by hyperlipoproteinemia and to co-segregate with high low density lipoprotein (LDL) levels (PMID: 10807540 (2000)). 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, this variant is classified as likely pathogenic. -

Apr 17, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 04, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in patients with familial hypercholesterolemia referred for genetic testing at GeneDx and in published literature (PMID: 16250003, 17539906, 34037665, 34456049, 36299643); 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.(E92K); This variant is associated with the following publications: (PMID: 17539906, 37589137, 34037665, 34456049, 36299643, 16250003, 30583242, 34906454, 10807540) -

Aug 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

LDLR: PP1:Strong, PM1, PM2, PS4:Moderate -

Homozygous familial hypercholesterolemia

Pathogenic:1

Nov 17, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Glu113Lys variant in LDLR has been reported in at least 2 individuals with hypercholesterolemia, 1 individual with probable hypercholesterolemia, and segregated with disease in 7 affected relatives from 1 family (Wu 2000 PMID: 10807540, Fouchier 2005 PMID: 16250003, Taylor 2007 PMID: 17539906). It has also been identified in 0.002% (3/128566) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported by other clinical laboratories in ClinVar (Variation ID: 237872). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant familial hypercholesterolemia (FH). ACMG/AMP Criteria applied: PP1_Strong, PM2_Supporting, PS4_Supporting. -

Cardiovascular phenotype

Uncertain:1

Feb 18, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.E113K variant (also known as c.337G>A), located in coding exon 4 of the LDLR gene, results from a G to A substitution at nucleotide position 337. The glutamic acid at codon 113 is replaced by lysine, an amino acid with similar properties. This alteration was reported to segregate with elevated LDL-C levels in one family (Wu LL et al. J. Hum. Genet., 2000;45:154-8). In addition, this alteration has been reported in familial hypercholesterolemia (FH) cohorts (Fouchier SW et al. Hum. Mutat., 2005 Dec;26:550-6; Taylor A et al. Clin. Genet., 2007 Jun;71:561-8). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.18

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

D;.;.;.

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.20

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D;D

M_CAP

Pathogenic

0.56

MetaRNN

Pathogenic

0.87

D;D;D;D

MetaSVM

Uncertain

0.58

MutationAssessor

Uncertain

2.1

M;.;.;M

PhyloP100

2.7

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-2.8

D;D;N;D

REVEL

Pathogenic

0.66

Sift

Benign

0.069

T;D;T;T

Sift4G

Uncertain

0.047

D;T;T;D

Polyphen

0.055

B;.;.;.

Vest4

0.49

MutPred

0.79

Gain of methylation at E113 (P = 0.003);Gain of methylation at E113 (P = 0.003);.;Gain of methylation at E113 (P = 0.003);

MVP

1.0

MPC

0.46

ClinPred

0.63

GERP RS

1.7

PromoterAI

-0.013

Neutral

(source)

Varity_R

0.47

gMVP

0.97

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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