rs200990725

Positions:

chr19-11106639-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R257L) has been classified as Likely benign.

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:10B:6

Conservation

PhyloP100: -1.40

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28213972).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.769C>T	p.Arg257Trp	missense_variant	5/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.769C>T	p.Arg257Trp	missense_variant	5/18	1	NM_000527.5	ENSP00000454071	P3	P01130-1

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

GnomAD3 exomes

AF:

0.0000954

AC:

AN:

251486

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135920

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 SAS exome

AF:

0.00

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000985

AC:

AN:

152264

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000524

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00135

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000118

Hom.:

Bravo

AF:

0.0000793

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:10Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:1Uncertain:5Benign:3

Uncertain significance, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Uncertain significance, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	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. -
Likely benign, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	Jan 02, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Jan 31, 2024	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). -
Uncertain significance, criteria provided, single submitter	research	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	Mar 03, 2019	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	Dec 16, 2016	subjects mutated among 2600 FH index cases screened = 2 / in association with c.1765G>A, p.Asp589Asn / Software predictions: Benign -

Familial hypercholesterolemia

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 30, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 08, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 09, 2022	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: 29365890). 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. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 08, 2024	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) -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 13, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 18, 2024	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. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 11, 2024

The p.R257W variant (also known as c.769C>T), located in coding exon 5 of the LDLR gene, results from a C to T substitution at nucleotide position 769. The arginine at codon 257 is replaced by tryptophan, an amino acid with dissimilar properties. This variant (also referred to as p.R236W) has been previously described in several individuals with familial hypercholesterolemia (FH) from various ethnic backgrounds, often along with the LDLR p.D589N variant (Nauck MS et al. Hum Mutat. 2001;18:165-6; Salazar LA et al. Hum Mutat. 2002;19:462-3; Fouchier SW et al. Hum Mutat. 2005;26:550-6; Chiou KR et al. Am J Cardiol. 2010;105:1752-8; Han SM et al. PLoS ONE. 2015;10:e0126706; Pek SLT et al. Atherosclerosis, 2018 Feb;269:106-116). In functional in vitro analyses, the p.R257W variant has demonstrated similar effects as the wild-type, including low-density lipoprotein receptor (LDLR) expression and the ability to bind and internalize LDL (Etxebarria A et al. Atherosclerosis. 2015;238:304-12). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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

0.17

BayesDel_addAF

Benign

-0.022

BayesDel_noAF

Uncertain

0.12

CADD

Benign

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

MutationTaster

Benign

1.0

D;N;N;N;N;N;N

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over