19-11102714-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS3_SupportingPM2PP3PP4PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.241C>T (p.Arg81Cys) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP4, PP3, PS4_supporting, and PS3_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 = 0.00001758 (0.001758%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1).PP3 - REVEL = 0.817PP4 - Variant meets PM2 and is identified 1 case with Simon-Broome possible from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge.PS3_supporting - Level 3 assay: PMID 25647241. HeLa cells, alternative microscopy assay, results - LDL-uptake 68%.PS4_supporting - Variant meets PM2 and is identified in 5 index cases (2 cases with DLCN criteria>=6 from in PMID:33418990 (Meshkov et al., 2021); at least 1 case with DLCN definite in PMID:11810272 (Fouchier et al., 2001); 1 case with DLCN definite in PMID:9712531 (Nissen et al., 1998); 1 case with Simon-Broome possible from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge). LINK:https://erepo.genome.network/evrepo/ui/classification/CA023666/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:19U:5O:1

Conservation

PhyloP100: 4.83

Publications

11 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: Likely_pathogenic. The variant received 6 ACMG points.

PS3

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

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5 link	c.241C>T	p.Arg81Cys	missense_variant	Exon 3 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.241C>T	p.Arg81Cys	missense_variant	Exon 3 of 18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152164

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00000795

AC:

AN:

251492

AF XY:

0.00000736

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:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461716

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727178

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000117

AC:

AN:

1111902

Other (OTH)

AF:

0.0000166

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

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:

0.00000657

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000195

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:19Uncertain:5Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:9Uncertain:4

Sep 18, 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.Arg60Cys in the mature protein) replaces arginine with cysteine at codon 81 in the LDLR type A repeat 2 of the LDLR protein. 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). Experimental functional studies using both transfected LDLR-deficient CHO-ldlA7 cells and a high-throughput assay have shown that this variant has an uncertain impact on LDLR activity (PMID: 25647241, 35568682). This variant has been reported in over 15 individuals affected with familial hypercholesterolemia (PMID: 9712531, 10422804, 11810272, 17765246, 20506408, 21642693, 23375686, 28161202, 29353225, 30293936, 33418990, 33454241, 34037665, 36499307) and in an individual affected with premature myocardial infarction (PMID: 30637778). This variant has been identified in 2/251492 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

0/208 non-FH alleles -

Apr 28, 2023

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance:Likely pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000527.5(LDLR):c.241C>T (p.Arg81Cys) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP4, PP3, PS4_supporting, and PS3_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 = 0.00001758 (0.001758%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1). PP3 - REVEL = 0.817 PP4 - Variant meets PM2 and is identified 1 case with Simon-Broome possible from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. PS3_supporting - Level 3 assay: PMID 25647241. HeLa cells, alternative microscopy assay, results - LDL-uptake 68%. PS4_supporting - Variant meets PM2 and is identified in 5 index cases (2 cases with DLCN criteria>=6 from in PMID: 33418990 (Meshkov et al., 2021); at least 1 case with DLCN definite in PMID: 11810272 (Fouchier et al., 2001); 1 case with DLCN definite in PMID: 9712531 (Nissen et al., 1998); 1 case with Simon-Broome possible from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge). -

Apr 28, 2022

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2016

Fundacion Hipercolesterolemia Familiar

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Mar 01, 2016

Iberoamerican FH Network

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:literature only

- -

Jul 30, 2021

New York Genome Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The inherited c.241C>T (p.Arg81Cys) variant identified in the LDLR gene substitutes a moderately conserved Arginine for Cysteine atamino acid 81/861 (exon 3/18). This variant is also referred to as p.Arg60Cys in some literature. This variant is found with low frequency in gnomAD(v3.1.1)(1heterozygote, 0 homozygotes; allele frequency: 6.57e-6) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Damaging (SIFT; score:0.001) and Pathogenic (REVEL; score:0.8169) to the function of the canonical transcripts. This variant is reported as Pathogenic/Likely Pathogenic/Variant of Uncertain Significance in ClinVar (VarID:183083), and has been reported in many affected individuals in the literature [PMID:9712531, 23375686, 20506408, 25647241, others]. Functional studies suggest that the p.Arg81Cys variant may have a mild effect on function,although these studies were performed using overexpression methodology and require additional studies for validation [PMID:25647241]. Given its presence in >10 affected individuals in the literature, low frequency in population databases, and in silico algorithms prediction of a damaging effect, the inherited c.241C>T(p.Arg81Cys) variant identified in the LDLR gene is reported as Likely Pathogenic. -

Jan 10, 2018

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

- -

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 = 2 / Functional test / Software predictions: Damaging -

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

- -

Apr 29, 2022

MGZ Medical Genetics Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Familial hypercholesterolemia

Pathogenic:4Uncertain:1

Aug 20, 2019

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.241C>T (p.Arg81Cys) variant in the LDLR gene has been reported in multiple unrelated individuals and families with familial hypercholesterolemia (PMID: 9712531, 10422804, 11810272, 17765246, 19318025, 21642693, 23375686, 25487149) and is rare in population databases. Multiple lines of in silico algorithms have predicted this Arg81Cys change to be deleterious. Therefore, this c.241C>T (p.Arg81Cys) variant is classified as likely pathogenic. -

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has been previously reported in individuals with hypercholesterolemia (PMID: 23375686; 33740630; 32719484; 34037665). The c.241C>T (p.Arg81Cys) variant is located in the low-density lipoprotein (LDL) receptor class A repeat domain, which is important for high affinity binding to LDLR ligands (PMID: 3283935). A different change at the same amino acid residue (p.Arg81Ser) has been previously reported in individuals with hypercholesterolemia (PMID: 12124988). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0008% (2/251492). It affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.241C>T (p.Arg81Cys) variant is classified as Likely Pathogenic. -

Aug 11, 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 81 of the LDLR protein (p.Arg81Cys). This variant is present in population databases (rs730882078, gnomAD 0.002%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9712531, 11810272, 17765246, 21642693, 23375686, 29353225). This variant is also known as p.Arg60Cys. ClinVar contains an entry for this variant (Variation ID: 183083). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects LDLR function (PMID: 25647241). This variant disrupts the p.Arg81 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 21382890), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Apr 09, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant (also known as p.Arg60Cys in the mature protein) replaces arginine with cysteine at codon 81 in the LDLR type A repeat 2 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function. Functional studies have been inconclusive with regard to the impact of this variant on LDLR activity (PMID: 25647241, 35568682). This variant has been reported in over 15 individuals affected with familial hypercholesterolemia (PMID: 9712531, 10422804, 11810272, 17765246, 20506408, 21642693, 23375686, 28161202, 29353225, 30293936, 33418990, 33454241, 34037665, 36499307) and in an individual affected with premature myocardial infarction (PMID: 30637778). This variant has been identified in 2/251492 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

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.Arg81Cys variant in LDLR has been reported in at least 12 individuals (2 African, 1 Italian, 1 Malaysian, 1 Venezuelan, 6 Dutch, 1 Portuguese) with familial hypercholesterolemia (PMID: 11845603, 28161202, 29353225, 28895539, 10422804, 21642693, 9712531, 17765246, 11810272), and has been identified in 0.002% (2/113766) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs730882078). This variant has (also) been reported in ClinVar as having conflicting interpretations of pathogenicity (Variation ID: 183083). In vitro functional studies provide some evidence that the p.Arg81Cys variant may slightly impact protein function (PMID: 25647241). However, these types of assays may not accurately represent biological function. 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, PP3, PS3_supporting (Richards 2015). -

not provided

Pathogenic:3Other:1

Mar 30, 2025

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(R60C); This variant is associated with the following publications: (PMID: 25647241, 21642693, 23375686, 25487149, 9712531, 11810272, 17765246, 20506408, 30971288, 29353225, 28895539, 21382890, 23833242, 10422804, 19318025, 11845603, 33740630, 34037665, 32719484, 31447099, 35339733, 30637778, 35568682, 33454241, 34456049, 36105085, 37409534, 36499307, 37589137, 35910211, 22390909, 28161202, 29396260, 30312929, 33418990, 39931866, 30293936) -

Dept. of Genetics and Pharmacogenomics, Merck Research Labs

Significance:not provided

Review Status:no classification provided

Collection Method:in vitro

- -

Jul 11, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The LDLR c.241C>T (p.Arg81Cys) variant has been reported in the published literature in multiple individuals with hypercholesterolemia (PMIDs: 9712531 (1998), 10422804 (1999), 17765246 (2008), 21642693 (2011), 23375686 (2013), 28161202 (2017), 29353225 (2018), 33418990 (2021), 33740630 (2021), 35339733 (2022), 36105085 (2022), 36499307 (2022), and 37589137 (2023)). It has also been reported in at least on individual with premature myocardial infarction (PMID: 30637778 (2019)). In vitro functional studies indicated that this variant has an inconclusive effect on LDLR protein function (PMIDs: 25647241 (2015) and 35568682 (2022)). The frequency of this variant in the general population, 0.000008 (2/251492 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, this variant is classified as likely pathogenic. -

Dec 16, 2019

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Homozygous familial hypercholesterolemia

Pathogenic:1

Mar 22, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg81Cys variant in LDLR (also described as p.Arg60Cys in the literature) has been reported in >18 individuals with familial hypercholesterolemia (FH; Nissen 1998 PMID: 9712531, Loubser 1999 PMID: 10422804, Fouchier 2001 PMID: 11810272, Bourbon 2008 PMID: 17765246, Alonso 2009 PMID: 19318025, Huijgen 2010 PMID: 20506408, Huijgen 2011 PMID: 21642693, Bertolini 2013 PMID: 23375686), though not all individuals had extremely elevated LDL-cholesterol levels (Huijgen 2011 PMID: 21642693). It has been suggested that the p.Arg81Cys variant results in an LDLR protein that does not function as effectively as that produced by the wild-type allele, thus resulting in only modest LDL-cholesterol elevations (Huijgen 2010 PMID: 20506408). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 183083) and has been identified in 0.02% (2/113766) European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of FH in the general population. In vitro functional studies suggest that this variant does not have a clear impact on LDL uptake into cells (Thormaehlen 2015 PMID: 25647241). Computational prediction tools and conservation analysis are consistent with pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg81Cys variant is likely pathogenic. ACMG/AMP Criteria applied: PS4_Strong, PM2_supporting, PP3. -

Early-onset coronary artery disease

Pathogenic:1

Sep 06, 2016

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.241C>T (p.Arg81Cys) variant involves the alteration of a conserved nucleotide and results in a replacement of a large size and basic Arginine (R) with a medium size and polar Cysteine (C) located in the ligand binding domain of LDLR. 5/5 in silico tools predict a damaging outcome for this substitution. This variant was found in 1/121500 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0010005). It was observed in several FH patients indicating pathogenicity. In addition, a clinical diagnostic laboratory classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Mar 25, 2025

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R81C variant (also known as c.241C>T), located in coding exon 3 of the LDLR gene, results from a C to T substitution at nucleotide position 241. The arginine at codon 81, located in LDLR class A repeat 2, is replaced by cysteine, an amino acid with highly dissimilar properties. Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Villéger L. Hum Mutat. 2002;20(2):81-7). This particular cysteine alteration has been detected in multiple individuals with familial hypercholesterolemia (FH) from a variety of ethnic backgrounds (Nissen H et al. Clin. Genet., 1998 Jun;53:433-9; Loubser O et al. Clin. Genet., 1999 May;55:340-5; Bourbon M et al. Atherosclerosis, 2008 Feb;196:633-42; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Pek SLT et al. Atherosclerosis, 2018 02;269:106-116). This alteration has also been reported in myocardial infarction cohorts, and limited functional studies were inconclusive (Do R et al. Nature, 2015 Feb;518:102-6; Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855). This amino acid position is well 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

Pathogenic

0.60

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.94

D;.;.;.;.

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.79

T;T;T;T;T

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.94

D;D;D;D;D

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

3.1

M;.;M;M;M

PhyloP100

4.8

PrimateAI

Benign

0.37

PROVEAN

Pathogenic

-5.5

D;D;D;D;D

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0010

D;D;D;D;D

Sift4G

Uncertain

0.0080

D;D;D;D;D

Polyphen

1.0

D;.;.;.;.

Vest4

0.77

MutPred

0.78

Loss of MoRF binding (P = 0.0377);Loss of MoRF binding (P = 0.0377);Loss of MoRF binding (P = 0.0377);Loss of MoRF binding (P = 0.0377);Loss of MoRF binding (P = 0.0377);

MVP

0.98

MPC

0.94

ClinPred

1.0

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.81

gMVP

0.97

Mutation Taster

=2/98

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

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