rs185098634

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM2PP3PP4PS4_SupportingBS3_Supporting

This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR):c.1720C>T (p.Arg574Cys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PS4_supporting and BS3_supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 - PopMax MAF = 0.0001384 (0.01384%) in Other populations exomes+genomes (gnomAD v2.1.1).PP3 - REVEL = 0.967.PP4 - Variant meets PM2. Variant identified in 5 FH cases (1 case with Simon-Broome possible from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); 1 case with Dutch Lipid Clinic Network score ≥ 6 published in PMID:11462246; 1 case with Dutch Lipid Clinic Network score ≥ 6 published in PMID:29290422; 1 case with Dutch Lipid Clinic Network score ≥ 6 from Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca; 1 case with Simon-Broome register possible/definite published in PMID:26892515.PS4_supporting - Variant meets PM2. Variant identified in 5 unrelated index cases (1 case with Simon-Broome from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); 1 case with Dutch Lipid Clinic Network score ≥ 6 published in PMID:11462246; 1 case with Dutch Lipid Clinic Network score ≥ 6 published in PMID:29290422; 1 case with Dutch Lipid Clinic Network score ≥ 6 from Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca; 1 case with Simon-Broome register criteria published in PMID:26892515.BS3_supporting - PMID:25647241: Level 3 assay- study on HeLa-Kyoto cells, LDLR-GFP construct, WB + CLSM assays, whole cycle is above 100% of wild-type activity.- functional study is consistent with no damaging effect. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023561/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:9U:4O:1

Conservation

PhyloP100: 5.95

Publications

9 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 4 ACMG points.

PS4

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

PM2

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.

BS3

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.1720C>T	p.Arg574Cys	missense_variant	Exon 12 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 link	c.1720C>T	p.Arg574Cys	missense_variant	Exon 12 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000318

AC:

AN:

251482

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000615

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1461660

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727122

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.000356

AC:

AN:

5622

European-Non Finnish (NFE)

AF:

0.0000126

AC:

AN:

1111978

Other (OTH)

AF:

0.0000497

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

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:

0.0000328

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41562

American (AMR)

AF:

0.0000655

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.555

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000594

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:9Uncertain:4Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:4Uncertain:4

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:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:literature only

- -

Mar 07, 2022

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

NM_000527.5(LDLR):c.1720C>T (p.Arg574Cys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PS4_supporting and BS3_supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - PopMax MAF = 0.0001384 (0.01384%) in Other populations exomes+genomes (gnomAD v2.1.1). PP3 - REVEL = 0.967. PP4 - Variant meets PM2. Variant identified in 5 FH cases (1 case with Simon-Broome possible from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); 1 case with Dutch Lipid Clinic Network score greater than or equal to 6 published in PMID: 11462246; 1 case with Dutch Lipid Clinic Network score greater than or equal to 6 published in PMID: 29290422; 1 case with Dutch Lipid Clinic Network score greater than or equal to 6 from Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca; 1 case with Simon-Broome register possible/definite published in PMID: 26892515. PS4_supporting - Variant meets PM2. Variant identified in 5 unrelated index cases (1 case with Simon-Broome from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); 1 case with Dutch Lipid Clinic Network score greater than or equal to 6 published in PMID: 11462246; 1 case with Dutch Lipid Clinic Network score greater than or equal to 6 published in PMID: 29290422; 1 case with Dutch Lipid Clinic Network score greater than or equal to 6 from Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca; 1 case with Simon-Broome register criteria published in PMID: 26892515. BS3_supporting - PMID: 25647241: Level 3 assay - study on HeLa-Kyoto cells, LDLR-GFP construct, WB + CLSM assays, whole cycle is above 100% of wild-type activity. - functional study is consistent with no damaging effect. -

Jul 29, 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 replaces arginine with cysteine at codon 574 of the LDLR protein. This variant is also known as p.Arg553Cys in the mature protein. This variant alters a conserved arginine residue in the LDLR type B repeat 5 of the LDLR protein (a.a. 572-615), 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 (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A high-throughput experimental study has shown that this variant may not disrupt LDLR function (PMID: 25647241). This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 11462246, 15823288, 19318025, 19446849, 26892515, 27050191, 30293936, 34297352). This variant has been stated to segregate with disease in a German family, although detailed data from the family study has not been provided (PMID: 11462246). This variant has been identified in 10/282878 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg574His, is considered to be disease-causing (ClinVar variation ID: 251996), suggesting that arginine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -

May 24, 2021

Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

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.Arg574Cys variant in LDLR has been reported in 14 individuals with familial hypercholesterolemia (PMID: 29290422, 25647241, 22698793, 20145306, 25487149, 23375686, 11462246, 26892515, 19446849), and has been identified in 0.006% (8/129194) European non-Finnish chromosomes. 0.004% (1/25116) European Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs185098634). 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#: 183123). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_moderate, PM2_supporting, PP3 (Richards 2015). -

Dec 16, 2016

Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

subject mutated among 2600 FH index cases screened = 1, family member=1 /FH-Germany/software prediction damaging -

Mar 01, 2016

Fundacion Hipercolesterolemia Familiar

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Familial hypercholesterolemia

Pathogenic:3

May 12, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with cysteine at codon 574 of the LDLR protein. This variant is also known as p.Arg553Cys in the mature protein. This variant alters a conserved arginine residue in the LDLR type B repeat 5 of the LDLR protein (a.a. 572-615), 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. A high-throughput experimental study has shown that this variant may not disrupt LDLR function (PMID: 25647241). This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 11462246, 15823288, 19318025, 19446849, 26892515, 27050191, 30293936, 34297352). This variant has been stated to segregate with disease in a German family, although detailed data from the family study has not been provided (PMID: 11462246). This variant has been identified in 10/282878 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg574His, is considered to be disease-causing (ClinVar variation ID: 251996), suggesting that arginine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -

Dec 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 574 of the LDLR protein (p.Arg574Cys). This variant is present in population databases (rs185098634, gnomAD 0.005%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 11462246, 19446849, 20145306, 23375686, 25487149, 26892515). ClinVar contains an entry for this variant (Variation ID: 183123). 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%. This variant disrupts the p.Arg574 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20018285, 22698793, 28028493). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

May 29, 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.1720C>T (p.Arg574Cys) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 3.2e-05 in 251482 control chromosomes. c.1720C>T has been observed in the heterozygous multiple individuals affected with Familial Hypercholesterolemia (Nauck_2001, Leren_2021, Sharifi_2016, Martin-Campos_2018). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function. One study reports reduced binding ability and LDLR activity for this variant (Li_2023), while another study reports no damaging effect (Thormaehlen_2015). The following publications have been ascertained in the context of this evaluation (PMID: 37813054, 37589137, 23375686, 20145306, 38374534, 15823288, 33740630, 37496633, 30293936, 11462246, 35339733, 26892515, 25647241, 32466883). ClinVar contains an entry for this variant (Variation ID: 183123). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1Other:1

Oct 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

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

- -

Cardiovascular phenotype

Pathogenic:1

Feb 26, 2020

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R574C variant (also known as c.1720C>T), located in coding exon 12 of the LDLR gene, results from a C to T substitution at nucleotide position 1720. The arginine at codon 574 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been detected in at least five individuals meeting clinical criteria for familial hypercholesterolemia (FH) as well as once in a cohort of individuals who experienced a myocardial infarction (MI) event before age 50 (Sharifi M et al. Metab. Clin. Exp., 2016 Mar;65:48-53; Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855; Do R et al. Nature, 2015 Feb;518:102-6; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Chmara M et al. J. Appl. Genet., 2010;51:95-106; Guardamagna O et al. J. Pediatr., 2009 Aug;155:199-204.e2; Nauck MS et al. Hum. Mutat., 2001 Aug;18:165-6). In addition, a different alteration located at the same position, p.R574S, has been detected in multiple individuals meeting clinical criteria for familial hypercholesterolemia (FH) (Paththinige CS et al. Lipids Health Dis, 2018 May;17:100; Du R et al. Springerplus, 2016 Dec;5:2095; Xiang R et al. Atherosclerosis, 2017 03;258:84-88); Ma Y et al. J Clin Lipidol Oct;12:230-235.e6). 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

0.55

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

D;.;.;.;.;.

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D;D;D;D

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.9

H;.;.;.;.;H

PhyloP100

5.9

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-7.6

D;D;D;D;D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.90

MVP

1.0

MPC

0.95

ClinPred

1.0

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.92

gMVP

0.99

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over