rs200990725

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM1PP2BP4BP6

The NM_000527.5(LDLR):c.769C>T(p.Arg257Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000353 in 1,614,128 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R257Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:11B:6

Conservation

PhyloP100: -1.40

Publications

32 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 1 ACMG points.

PM1

In a hotspot region, there are 21 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 13 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=0.28213972).

BP6

Variant 19-11106639-C-T is Benign according to our data. Variant chr19-11106639-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 251446.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5 link	c.769C>T	p.Arg257Trp	missense_variant	Exon 5 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.769C>T	p.Arg257Trp	missense_variant	Exon 5 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00135

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:

0.0000954

AC:

AN:

251486

AF XY:

0.000125

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000979

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000287

AC:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.000112

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000126

AC:

AN:

1111986

Other (OTH)

AF:

0.0000331

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

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:

0.0000985

AC:

AN:

152264

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41556

American (AMR)

AF:

0.000524

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00135

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.0000228

Hom.:

Bravo

AF:

0.0000793

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:11Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:1Uncertain:5Benign:3

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:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

subjects mutated among 2600 FH index cases screened = 2 / in association with c.1765G>A, p.Asp589Asn / Software predictions: Benign -

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Jan 02, 2018

Robarts Research Institute, Western University

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:criteria provided, single submitter

Collection Method:literature only

- -

Aug 13, 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 (also known as p.Arg236Trp in the mature protein) is located in the sixth LDLR type A repeat in the ligand binding domain 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). Functional studies have demonstrated that the variant protein shows normal LDLR expression at the cell surface and normal LDL binding and uptake activity (PMID: 25545329). This variant has been reported in many individuals affected with or suspected of having familial hypercholesterolemia in Brazil, China, Germany, Korea and the Netherlands (PMID: 11462246, 11933210, 16250003, 20538126, 22353362, 25461735, 25962062, 26343872, 32759540, 33994402, 34456200, 34573395, 35137788). In two Chinese brothers with severe hypercholesterolemia, this variant co-occurred with two other heterozygous variants in LDLR (p.Gln191* and p.Asp589Asn) (PMID: 29399563). This variant and p.Asp589Asn have been reported to occur on the same allele (PMID: 16250003, 18325082). This variant has been identified in 26/282894 chromosomes (20/19954 East Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Functional studies and relatively high allele frequency in the general population indicate that this variant is unlikely to cause disease. However, additional studies are necessary 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:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant LDLR:c.769C>T (also known as p.Arg236Trp in the mature protein), replaces a arginine with tryptophan at codon 257 of the LDLR protein (p.Arg257Trp). 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 reclassified as “Likely Benign” from evidence as follows. It is located within a conserved (REVEL=0.648) functional domain (LDLR Class A6) involved in LDL binding with LDL receptors. Because this variant is observed with a frequency <0.02% in the general population (GnomAD= 0.0000985, no homozygotes) multiple reports classify this variant as VUS (PM2). However, despite apparent cosegregation in several independent FH families, it has been frequently observed in normolipidemic individuals (BS2) or in Cis with other proven pathogenic variants in FH patients (BP2). Finally, several independent level 1 in-vitro functional studies have shown consistently that this variant has a neutral effect on LDLR function (BS3). -

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 03, 2019

Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Mar 01, 2016

Fundacion Hipercolesterolemia Familiar

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

not provided

Uncertain:4

Jul 08, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in multiple unrelated patients from different ethnic backgrounds with familial hypercholesterolemia (FH) in the published literature (PMID: 26690388, 32759540, 11462246, 11933210, 16250003, 19318025, 20538126, 25962062, 25461735, 26343872, 26875521, 29353225, 30526649, 30293936, 30592178, 34573395); Many individuals with p.R257W in the published literature harbor a second variant in LDLR (p.D589N) in cis, including two individuals homozygous for both variants; these variants are suspected to be linked on the same allele (PMID: 16250003, 20538126, 25962062, 29399563, 30795984, 33994402); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(R236W); This variant is associated with the following publications: (PMID: 30592178, 29083407, 29353225, 30526649, 30293936, 11462246, 20538126, 26332594, 11933210, 25461735, 25962062, 26343872, 19318025, 26875521, 22353362, 25545329, 16250003, 32041611, 32719484, 35538921, 30400955, 29399563, 35999587, 18325082, 35560019, 26690388, 32759540, 34573395, 30795984, 33994402, 34456200) -

Sep 13, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The LDLR c.769C>T; p.Arg257Trp variant (rs200990725, ClinVar Variation ID 251446) is reported along with another LDLR variant, c.1765G>A; p.Asp589Asn, as linked variants in individuals affected with hypercholesterolemia (Gratton 2023, Huang 2022, Olfson 2015). Affected individuals had an additional variant in trans (on opposite chromosome) to these linked LDLR variants. LDLR Arg257Trp is found predominantly in the East Asian population with an allele frequency of 0.1% (20/19954 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.648). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Gratton J et al. Prevalence of FH-Causing Variants and Impact on LDL-C Concentration in European, South Asian, and African Ancestry Groups of the UK Biobank-Brief Report. Arterioscler Thromb Vasc Biol. 2023 Sep. PMID: 37409534. Huang CC et al. Genetic Analysis in a Taiwanese Cohort of 750 Index Patients with Clinically Diagnosed Familial Hypercholesterolemia. J Atheroscler Thromb. 2022 May 1. PMID: 33994402. Olfson E et al. Identification of Medically Actionable Secondary Findings in the 1000 Genomes. PLoS One. 2015 PMID: 26332594. -

Oct 19, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The LDLR c.769C>T (p.Arg257Trp) variant (also known as R257W and R236W) has been reported in the published literature in multiple individuals affected with hypercholesterolemia (PMIDs: 11462246 (2001), 11933210 (2002), 19318025 (2009), 22353362 (2012), 25461735 (2015), 29353225 (2018), 29399563 (2018), 30293936 (2018), 31345425 (2019), 32759540 (2020), 34573395 (2021), 35137788 (2022)). In addition, this variant is often seen together with another LDLR variant, c.1765G>A (p.Asp589Asn). When this complex allele occurs in the homozygous phase or in trans with other deleterious LDLR variants, c.986G>A (p.Cys329Tyr) or c.1754T>A (p.Ile585Asn), the phenotype appears more severe and is suggestive of homozygous hypercholesterolemia (HoFH) (PMIDs: 30795984 (2019), 25962062 (2015), 20538126 (2010)). A functional study, however, indicated that the c.769C>T (p.Arg257Trp) variant showed normal levels of LDLR protein expression as well as normal LDL binding and uptake activity (PMID: 25545329 (2015)). Another report described the variant to retain 85% activity (PMID: 27206935 (2016)) and further research is necessary. The frequency of this variant in the general population, 0.0012 (18/14424 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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, we are unable to determine the clinical significance of this variant. -

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial hypercholesterolemia

Uncertain:1Benign:2

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 31, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with tryptophan at codon 257 in the sixth LDLR type A repeat in the ligand binding domain of the LDLR protein. This variant is also known as p.Arg236Trp in the mature protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. Functional studies have demonstrated that the variant protein shows normal LDLR expression at the cell surface and normal LDL binding and uptake activity (PMID: 25545329). This variant has been reported in many individuals affected with or suspected of having familial hypercholesterolemia in Brazil, China, Germany, Korea and the Netherlands (PMID: 11462246, 11933210, 16250003, 20538126, 22353362, 25461735, 25962062, 26343872, 32759540, 33994402, 34456200, 34573395, 35137788, 38003014). In two Chinese siblings with severe hypercholesterolemia, this variant co-occurred with two other heterozygous variants in LDLR (p.Gln191* and p.Asp589Asn) (PMID: 29399563). This variant and p.Asp589Asn have been reported to occur on the same allele (PMID: 16250003, 18325082). This variant has been identified in 26/282894 chromosomes (20/19954 East Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Functional studies and relatively high allele frequency in the general population indicate that this variant is unlikely to cause disease. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Oct 08, 2020

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Cardiovascular phenotype

Uncertain:1

May 12, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.769C>T (p.R257W) alteration is located in exon 5 (coding exon 5) of the LDLR gene. This alteration results from a C to T substitution at nucleotide position 769, causing the arginine (R) at amino acid position 257 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Jun 18, 2024

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: LDLR c.769C>T (p.Arg257Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.5e-05 in 251486 control chromosomes, predominantly at a frequency of 0.00098 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (9.5e-05 vs 0.0013), allowing no conclusion about variant significance. c.769C>T has been reported in the literature in individuals affected with Familial Hypercholesterolemia without strong evidence of causality (e.g. Luirink_2019, Huang_2022, Kim_2022). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Etxebarria_2015). The following publications have been ascertained in the context of this evaluation (PMID: 25545329, 30795984, 34456200, 33994402). ClinVar contains an entry for this variant (Variation ID: 251446). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.022

BayesDel_noAF

Uncertain

0.12

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

D;.;.;.;.

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.89

D;D;D;T;D

M_CAP

Pathogenic

0.52

MetaRNN

Benign

0.28

T;T;T;T;T

MetaSVM

Uncertain

0.43

MutationAssessor

Benign

1.7

L;.;.;.;L

PhyloP100

-1.4

PrimateAI

Benign

0.22

PROVEAN

Uncertain

-3.5

D;D;D;D;D

REVEL

Pathogenic

0.65

Sift

Uncertain

0.0060

D;D;D;D;D

Sift4G

Uncertain

0.010

D;D;D;D;D

Polyphen

0.99

D;.;.;.;.

Vest4

0.45

MVP

1.0

MPC

0.25

ClinPred

0.17

GERP RS

0.38

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.54

gMVP

0.83

Mutation Taster

=20/80

disease causing (ClinVar)

(source)

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

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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