NM_000527.5:c.622G>A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_000527.5(LDLR):c.622G>A(p.Glu208Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,382 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 Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 5.49

Publications

23 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 17 ACMG points.

PM1

In a hotspot region, there are 30 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_000527.5

PM2

Very rare variant in population databases, with high coverage;

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.972

PP5

Variant 19-11105528-G-A is Pathogenic according to our data. Variant chr19-11105528-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 251328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5 link	c.622G>A	p.Glu208Lys	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.622G>A	p.Glu208Lys	missense_variant	Exon 4 of 18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461382

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726996

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:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53018

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111940

Other (OTH)

AF:

0.00

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:5

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:literature only

- -

Jul 18, 2022

MGZ Medical Genetics Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2020

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This c.622G>A (p.Glu208Lys) variant in the LDLR gene has been reported in multiple individuals with familial hypercholesterolemia (PMID: 1301956, 9767373, 11810272, 22390909, 21722902). Functional studies have demonstrated a deleterious effect of the p.Glu208Lys variant on LDL binding (PMID: 1301956, 18677035). This variant is not present in the general population (gnomAD). Multiple algorithms predicted this change to be deleterious. Therefore, the c.622G>A (p.Glu208Lys) variant in the LDLR gene is classified as pathogenic. -

Apr 28, 2023

All of Us Research Program, National Institutes of Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant is located in the fifth LDLR type A repeat in the ligand binding domain of the LDLR protein. This variant is also known as p.Glu187Lys in the mature protein and as FH Jerusalem in the literature. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study using cells from a heterozygous individual have demonstrated a significantly reduced LDLR activity (PMID: 1301956). This variant has been reported in multiple unrelated individuals diagnosed with familial hypercholesterolemia (PMID: 1301956, 8882879, 9767373, 11810272, 22390909, 32759540, 32770674, 33418990, 34037665, 34363016). This variant has also been observed in homozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 35249492). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic. -

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

not provided

Pathogenic:3

Clinical Genetics, Academic Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 21, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate that this variant, reported as E187K, has a damaging effect on LDL binding affinity and B-VLDL binding affinity (PMID: 18677035, 1301956); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.E187K and FH-Jerusalem; This variant is associated with the following publications: (PMID: 22390909, 1301956, 11810272, 9767373, 8882879, 32770674, 33740630, 33418990, 34037665, 34363016, 32759540, 35249492, 30583242, 34906454, 2799589, 18677035) -

Familial hypercholesterolemia

Pathogenic:3

Aug 28, 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 208 of the LDLR protein (p.Glu208Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypercholesterolaemia (PMID: 1301956, 22390909). This variant is also known as p.Glu187Lys. ClinVar contains an entry for this variant (Variation ID: 251328). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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). For these reasons, this variant has been classified as Pathogenic. -

Mar 08, 2023

Color Diagnostics, LLC DBA Color Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 14, 2025

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.622G>A (p.Glu208Lys) results in a conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant was absent in 250814 control chromosomes (gnomAD). c.622G>A has been observed in multiple individuals affected with Familial Hypercholesterolemia (e.g. Meshkov_2021, Alnouri_2022). 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: 35249492, 33418990). ClinVar contains an entry for this variant (Variation ID: 251328). Based on the evidence outlined above, the variant was classified as pathogenic. -

Homozygous familial hypercholesterolemia

Pathogenic:1

Mar 16, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Glu208Lys variant in LDLR (also described as p.Glu187Lys and FH Jerusalem in the literature) has been reported in >30 individuals with hypercholesterolemia, segregated with disease in 9 affected relatives from 3 families (Kotze 1989, Hobbs 1992, Ekstrom 1998, Fouchier 2001, Fouchier 2015), and was absent from large population studies. This variant has been reported in ClinVar (Variation ID: 251328). Functional studies provide some evidence that the p.Glu208Lys variant reduces protein activity (Hobbs 1992). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for hypercholesterolemia in an autosomal dominant manner based upon segregation studies, absence from controls, and functional evidence. ACMG/AMP Criteria applied: PS4; PP1_Strong; PM2; PS3_Supporting. -

LDLR-related disorder

Pathogenic:1

Jan 24, 2023

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The LDLR c.622G>A variant is predicted to result in the amino acid substitution p.Glu208Lys. This variant was reported in multiple individuals with familial hypercholesterolemia (reported as E187K in Table 2, Hobbs et al 1992. PubMed ID: 1301956; Table 1, Huijgen et al 2012. PubMed ID: 22390909; Table 4, Wang et al 2020. PubMed ID: 32759540; Table S5, Rieck et al 2020. PubMed ID: 32770674; Table A1, Meshkov et al 2021. PubMed ID: 33418990; Table S1, Leren TP et al 2021. PubMed ID: 33740630; e-Table 1, Sturm AC et al 2021. PubMed ID: 34037665). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Aug 30, 2017

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.E208K variant (also known as c.622G>A), located in coding exon 4 of the LDLR gene, results from a G to A substitution at nucleotide position 622. The glutamic acid at codon 208 is replaced by lysine, an amino acid with similar properties, and is located in the ligand-binding domain. This alteration, also known as E187K, has been reported in multiple individuals with familial hypercholesterolemia (FH) from a variety of ethnic backgrounds, including an affected father-son pair; compound heterozygote cases with this alteration were also reported (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Reshef A et al. Hum. Genet., 1996 Nov;98:581-6; Fouchier SW et al. Hum. Genet., 2001 Dec;109:602-15; Huijgen R et al. Eur. Heart J., 2012 Sep;33:2325-30). One in vitro study demonstrated a ten-fold reduction in beta-VLDL binding with this alteration (Zhao Z et al. J. Biol. Chem., 2008 Sep;283:26528-37). 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 majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.78

D;.;.;.

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Pathogenic

0.94

MutationAssessor

Benign

1.2

L;.;.;L

PhyloP100

5.5

PrimateAI

Uncertain

0.48

PROVEAN

Uncertain

-3.4

D;D;D;D

REVEL

Pathogenic

0.81

Sift

Benign

0.088

T;T;T;T

Sift4G

Uncertain

0.056

T;D;T;T

Polyphen

0.98

D;.;.;.

Vest4

0.79

MutPred

0.89

Gain of methylation at E208 (P = 0.0073);Gain of methylation at E208 (P = 0.0073);.;Gain of methylation at E208 (P = 0.0073);

MVP

1.0

MPC

0.54

ClinPred

0.97

GERP RS

5.6

PromoterAI

-0.0018

Neutral

(source)

Varity_R

0.76

gMVP

0.92

Mutation Taster

=3/97

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over