rs140241383

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PS4_SupportingPP3PP1PP4

This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR):c.858C>A (p.Ser286Arg) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PS4_Supporting, PP1, PP3 and PP4) 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 = 0.00006155 (0.006155%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1).PS4_Supporting - Variant meets PM2 and is identified in 4 unrelated index cases who fulfil DLCN >=6 (1 case in PMID:32770674; 2 cases from Robarts Research Institute) or SB definitive ( 1 case from Molecular Genetics Laboratory of Centre for Cardiovascular Surgery and Transplantation).PP1 - Variant segregates with FH phenotype in 2 informative meiosis from 2 unrelated families (1 case from Molecular Genetics Laboratory of Centre for Cardiovascular Surgery and Transplantation and 1 case from Robarts Research Institute).PP3 - REVEL = 0.766.PP4 - Variant meets PM2 and is identified in 4 index cases who fulfil DLCN >=6 (1 case in PMID:32770674; 2 cases from Robarts Research Institute) or SB definitive ( 1 case from Molecular Genetics Laboratory of Centre for Cardiovascular Surgery and Transplantation). LINK:https://erepo.genome.network/evrepo/ui/classification/CA029904/MONDO:0007750/013

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:27U:1

Conservation

PhyloP100: -1.35

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 Likely_pathogenic. Variant got 6 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.

PP1

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5 link	c.858C>A	p.Ser286Arg	missense_variant	Exon 6 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.858C>A	p.Ser286Arg	missense_variant	Exon 6 of 18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

251430

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135904

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1459096

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

725868

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000294

Hom.:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:27Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:15Uncertain:1

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 pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

subjects mutated among 2600 FH index cases screened = 6 / FH-Greece-2, 5 to 15% LDLR Activity / Software predictions: Conflicting -

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

May 28, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ser286Arg variant in LDLR has been reported in more than 25 individuals with hypercholesterolemia and segregated with disease in at least 27 affected individuals from multiple families (Hobbs 1992 PMID: 1301956, Bertolini 2013 PMID: 23375686, Mollaki 2014 PMID: 27578104). Notably, the variant appears to be associated with a milder hypercholesterolemia phenotype (Huijgen 2012 PMID: 22390909). This variant has also been reported in by other clinical laboratories in ClinVar (Variation ID 251488) and has been identified in 0.006% (7/113726) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of familial hypercholesterolemia (FH) in the general population. In vitro functional studies support an impact on protein function (Hobbs 1992 PMID: 1301956) and computational prediction tools and conservation analyses are consistent with pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2_supporting, PS3_Supporting, PP3. -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

May 23, 2019

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Sep 21, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with familial hypercholesterolaemia 1 (FH; MIM#143890). (I) 0108 - This gene is associated with both recessive and dominant disease. Variants have been reported in heterozygous, compound heterozygous and homozygous states with the recessive disease being more severe (OMIM, PMID: 10978268). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 24404629). (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (7 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Ldl_recept_a domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as likely pathogenic or pathogenic (ClinVar). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Jun 08, 2023

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.77; 3Cnet: 0.94). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000251488 /PMID: 1301956). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Feb 14, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 30, 2017

U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 05, 2022

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM1, PM2, PP2, PP3, PP5 -

May 16, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Robarts Research Institute, Western University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 19, 2022

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

NM_000527.5(LDLR):c.858C>A (p.Ser286Arg) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PS4_Supporting, PP1, PP3 and PP4) 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 = 0.00006155 (0.006155%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1). PS4_Supporting - Variant meets PM2 and is identified in 4 unrelated index cases who fulfil DLCN >=6 (1 case in PMID: 32770674; 2 cases from Robarts Research Institute) or SB definitive ( 1 case from Molecular Genetics Laboratory of Centre for Cardiovascular Surgery and Transplantation). PP1 - Variant segregates with FH phenotype in 2 informative meiosis from 2 unrelated families (1 case from Molecular Genetics Laboratory of Centre for Cardiovascular Surgery and Transplantation and 1 case from Robarts Research Institute). PP3 - REVEL = 0.766. PP4 - Variant meets PM2 and is identified in 4 index cases who fulfil DLCN >=6 (1 case in PMID: 32770674; 2 cases from Robarts Research Institute) or SB definitive ( 1 case from Molecular Genetics Laboratory of Centre for Cardiovascular Surgery and Transplantation). -

Nov 05, 2016

Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 14, 2023

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 (also known as p.Ser265Arg in the mature protein and as FH Greece-2) replaces serine with arginine at codon 286 in the LDLR type A repeat 7 of the ligand binding domain of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An experimental functional study has shown that this variant in compound heterozygosity with p.Cys173Arg reduces LDLR activity to 5-15% compared to wild type (PMID: 1301956). This variant has been reported in numerous individuals affected with familial hypercholesterolemia (PMID: 11462246, 11810272, 15015036, 17347910, 23130880, 27578104, 27765764, 28965616, 32829317, 33454241, 33794673; Color Health internal data) and is a recurrent mutation in the Greek population (PMID: 27578104). This variant has been identified in 7/251430 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

not provided

Pathogenic:7

Aug 15, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect, including a reduction in LDLR activity (Hobbs et al., 1992); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 14974088, 22390909, 15015036, 11462246, 23375686, 27578104, 25463123, 28965616, 34426522, 33303402, 32719484, 32770674, 32977124, 34037665, 1301956) -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LDLR: PM1, PM2, PP4:Moderate, PS4:Moderate -

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 01, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM2_supporting, PS3_moderate, PS4 -

Jul 25, 2022

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4, PP3, PM2_SUP -

Jun 11, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LDLR c.858C>A (p.Ser286Arg) variant has been reported in the published literature in multiple families affected with hypercholesterolemia (PMID: 11462246 (2001), 15015036 (2004), 17347910 (2007), 21925044 (2011), 26361156 (2015), 27765764 (2016), 32770674 (2020), 32977124 (2020), 33794673 (2021), 37409534 (2023)), though it has been reported to produce milder phenotype (PMID: 25463123 (2014)). In a published functional study, this variant resulted in a significant reduction in LDLR activity (PMID: 1301956 (1992)). The frequency of this variant in the general population, 0.000062 (7/113726 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with 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, this variant is classified as pathogenic. -

Familial hypercholesterolemia

Pathogenic:4

Jan 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 286 of the LDLR protein (p.Ser286Arg). This variant is present in population databases (rs140241383, gnomAD 0.007%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 1301956, 11317361, 11462246, 15015036, 23130880, 27765764). 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.Ser265Arg. ClinVar contains an entry for this variant (Variation ID: 251488). 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%. For these reasons, this variant has been classified as Pathogenic. -

Nov 02, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces serine with arginine at codon 286 in the LDLR type A repeat 7 of the ligand binding domain of the LDLR protein. This variant is also known as p.Ser265Arg in the mature protein and as FH Greece-2 in the literature. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An experimental functional study has shown that this variant in compound heterozygosity with p.Cys173Arg reduces LDLR activity to 5-15% compared to wild type (PMID: 1301956). This variant has been reported in over 150 individuals affected with familial hypercholesterolemia (PMID: 11462246, 11810272, 15015036, 17347910, 23130880, 27578104, 27765764, 28965616, 32829317, 33454241, 33794673; Color Health internal data) and is a recurrent mutation in the Greek population (PMID: 27578104). This variant has been identified in 7/251430 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Jan 23, 2025

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 06, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The LDLR c.858C>A (p.Ser286Arg) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index), which was confirmed by low LDLR activity in patient carrying this variant (Hobbs_1992). This variant was found in 3/121368 control chromosomes at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). This variant has been reported in a large number of FH patients with milder phenotype. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic. -

Cardiovascular phenotype

Pathogenic:1

May 03, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S286R pathogenic mutation (also known as c.858C>A), located in coding exon 6 of the LDLR gene, results from a C to A substitution at nucleotide position 858. The serine at codon 286 is replaced by arginine, an amino acid with dissimilar properties, and is located in the ligand binding 7 domain. This alteration, also referred to as S265R and FH Greece-2, has been detected in several cohorts and multiple unrelated individuals with hypercholesterolemia from various ethnic backgrounds, and has been reported to result in reduced LDL receptor activity (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Day IN et al. Hum. Mutat., 1997;10:116-27; Traeger-Synodinos J et al. Hum. Genet., 1998 Mar;102:343-7; Nauck MS et al. Hum. Mutat., 2001 Aug;18:165-6; Mihaylov VA et al. J. Hum. Genet., 2004 Mar;49:173-6; Whittall RA et al. Ann. Clin. Biochem., 2010 Jan;47:44-55; Huijgen R et al. Eur. Heart J., 2012 Sep;33:2325-30; Mollaki V et al. Atherosclerosis, 2014 Dec;237:798-804; Klanar G et al. J. Am. Coll. Cardiol., 2015 Sep;66:1250-1257). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.43

CADD

Benign

6.7

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.86

D;.;.;.;.;.

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.41

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.82

D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.4

M;.;.;.;.;M

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.9

D;D;D;D;D;D

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0030

D;D;D;D;D;D

Sift4G

Uncertain

0.018

D;D;D;D;D;D

Polyphen

0.99

D;.;.;.;.;.

Vest4

0.67

MutPred

0.66

Gain of ubiquitination at K283 (P = 0.0798);Gain of ubiquitination at K283 (P = 0.0798);.;.;.;Gain of ubiquitination at K283 (P = 0.0798);

MVP

1.0

MPC

0.85

ClinPred

0.80

GERP RS

-6.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.89

gMVP

0.91

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