rs201971888

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got -1 ACMG points: 0P and 1B. BP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1765G>A (p.Asp589Asn) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes BP4 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:BP4 - REVEL = 0.325. It is below 0.5, splicing evaluation needed. Functional data on splicing not available.A) variant not on limits.B) does not create AG or GTVariant is not predicted to alter splicing LINK:https://erepo.genome.network/evrepo/ui/classification/CA036508/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:16

Conservation

PhyloP100: 3.01

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.

BP4

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.1765G>A	p.Asp589Asn	missense_variant	Exon 12 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.1765G>A	p.Asp589Asn	missense_variant	Exon 12 of 18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00116

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:

0.0000835

AC:

AN:

251490

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00109

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1461818

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000529

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ExAC

AF:

0.0000576

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:16

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:1Uncertain:7

Feb 24, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiology Department, Cho Ray Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 35-year-old male patient was admitted with a high LDL-C level of 435 mg/dL and a confirmed diagnosis of triple vessel coronary artery disease. Medical history: dyslipidemia, myocardial infarction at age 34. Family history: Biological father died of a myocardial infarction at the age of 45. Genetic diagnosis: homozygote variants of LDLR c.1765G>A (p.Asp589Asn). -

Jan 02, 2018

Robarts Research Institute, Western University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 29, 2022

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000527.5(LDLR):c.1765G>A (p.Asp589Asn) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes BP4 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: BP4 - REVEL = 0.325. It is below 0.5, splicing evaluation needed. Functional data on splicing not available. A) variant not on limits. B) does not create AG or GT Variant is not predicted to alter splicing -

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

- -

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.Asp568Asn in the mature protein) replaces aspartic acid with asparagine at codon 589 of the LDLR protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <=0.5, PMID: 27666373). This variant has been reported in several individuals affected with familial hypercholesterolemia in Korea, Taiwan, China and the Netherlands (PMID: 16250003, 25962062, 22353362, 20538126, 26343872, 30795984, 32629184, 32759540, 33994402, 34456200). It has also been reported in an individual affected with metabolic syndrome (PMID: 35999587). This variant has also been identified in 18/246268 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

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

- -

not provided

Uncertain:4

Dec 04, 2023

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: 18325082, 16250003, 20538126, 25962062, 26343872, 29353225, 30526649, 30592178, 30795984); Many individuals with p.(D589N) in the published literature harbor a second variant in LDLR (p.R257W) in cis, including two individuals homozygous for both variants (PMID: 25962062, 20538126, 34456200); these variants are suspected to be linked on the same allele; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(D568N); This variant is associated with the following publications: (PMID: 26332594, 29353225, 30526649, 30592178, 30795984, 22353362, 27206935, 26343872, 16250003, 29399563, 32629184, 20538126, 28502495, 34040191, 33740630, 35538921, 33994402, 32759540, 35999587, 34456200, 25962062, 18325082, 30400955) -

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.1765G>A (p.Asp589Asn) variant (also known as D589N and D568N) has been reported in the published literature in individuals affected with hypercholesterolemia as a lone variant (PMIDs: 29353225 (2018), 30270083 (2018), 33740630 (2021), 34040191 (2021)) and in multiple affected individuals co-occurring with the LDLR c.769C>T (p.Arg257Trp) variant (PMIDs: 16250003 (2005), 18325082 (2008), 22353362 (2012), 26343872 (2015), 28502495 (2017), 29353225 (2018), 29399563 (2018), 30270083 (2018), 30400955 (2018), 30592178 (2019), 33994402 (2021)). 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)). In addition, the variant was described as retaining 85% activity (PMID: 27206935 (2016)), however, further research is necessary. The frequency of this variant in the general population, 0.0014 (20/14424 chromosomes in Other East Asian subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. 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. -

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.1765G>A; p.Asp589Asn variant (rs201971888, ClinVar Variation ID 252022) is reported along with another LDLR variant, c.769C>T; p.Arg257Trp, 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 Asp589Asn is found predominantly in the East Asian population with an allele frequency of 0.1% (21/19950 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is neutral (REVEL: 0.325). 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. -

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:3

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 01, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant (also known as p.Asp568Asn in the mature protein) replaces aspartic acid with asparagine at codon 589 of the LDLR protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant has been reported in several individuals affected with familial hypercholesterolemia in Korea, Taiwan, China and the Netherlands (PMID: 16250003, 25962062, 22353362, 20538126, 26343872, 30795984, 32629184, 32759540, 33994402, 34456200). It has also been reported in an individual affected with metabolic syndrome (PMID: 35999587). This variant has also been identified in 18/246268 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 589 of the LDLR protein (p.Asp589Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 16250003, 20538126, 22353362, 25962062, 26343872, 27206935, 28502495, 29353225, 29399563, 30795984, 34040191). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. This variant is also known as p.Asp568Asn. ClinVar contains an entry for this variant (Variation ID: 252022). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Jun 18, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LDLR c.1765G>A (p.Asp589Asn) results in a conservative amino acid change in 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 8.4e-05 in 251490 control chromosomes, predominantly at a frequency of 0.0011 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 (8.4e-05 vs 0.0013), allowing no conclusion about variant significance. c.1765G>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia without strong evidence for causality, and often found along with c.769C>T (e.g. Chiou_2010, Chiou_2017, Sun_2018, Chan_2018, Huang_2022). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20538126, 30592178, 28502495, 30400955, 33994402). ClinVar contains an entry for this variant (Variation ID: 252022). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cardiovascular phenotype

Uncertain:1

Apr 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D589N variant (also known as c.1765G>A), located in coding exon 12 of the LDLR gene, results from a G to A substitution at nucleotide position 1765. The aspartic acid at codon 589 is replaced by asparagine, an amino acid with highly similar properties. This alteration (also referred to as p.D568N) has been reported in several familial hypercholesterolemia (FH) cohorts and is reported to occur with p.R257W on the same allele in some instances (Fouchier SW et al. Hum. Mutat., 2005 Dec;26:550-6; Chiou KR et al. Am. J. Cardiol., 2010 Jun;105:1752-8; Chiou KR et al. Gene, 2012 Apr;498:100-6; Shin DG et al. Atherosclerosis, 2015 Nov;243:53-8; Pek SLT et al. Atherosclerosis, 2018 Feb;269:106-116). 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 not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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

0.12

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.87

D;.;.;.;.;.

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.59

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.85

T;D;D;D;D;D

M_CAP

Pathogenic

0.35

MetaRNN

Benign

0.098

T;T;T;T;T;T

MetaSVM

Uncertain

0.064

MutationAssessor

Benign

1.4

L;.;.;.;.;L

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-4.4

D;D;D;D;D;D

REVEL

Uncertain

0.33

Sift

Benign

0.083

T;T;T;T;T;T

Sift4G

Benign

0.25

T;T;T;T;T;T

Polyphen

0.98

D;.;.;.;.;.

Vest4

0.36

MVP

1.0

MPC

0.33

ClinPred

0.38

GERP RS

2.2

Varity_R

0.40

gMVP

0.94

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