rs137853963

Variant names:

• chr19-11123264-G-A
• rs137853963
• NM_000527.5:c.2231G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PS3_Supporting BP4 BP2

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR): c.2231G>A (p.Arg744Gln) variant is classified as Likely benign for Familial Hypercholesterolemia by applying evidence codes BP4, BP2 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:BP4 - REVEL score is 0.291. It is below 0.5, so splicing evaluation is required. Functional data on splicing is not available. A) Variant not on limits. B) Variant is exonic and within range, but it does not create a de novo AG or GT site. The variant is not predicted to alter splicing.BP2 - 2 individuals from Ambry Genetics: Patient 1 has LDLR p.Gln33* in trans. Phenotype LDL 111 mg/dl (on treatment); Patient 2 has LDLR p.Gly373Asp in trans. Phenotype = "high chol".PS3_supporting - level 3 assay (PMID:9409298) - Heterozygous patients' lymphoblasts, immunoblotting, I125-LDL assay: no precursor detectable, degradation of 125I-LDL = 73%.Variant has 2 Supporting evidence codes towards Benign, enough to classify as Likely benign, and only 1 Supporting evidence code towards Pathogenic. The Benign criteria overwhelms the Pathogenic criteria, so we are confident in classifying this variant as Likely benign. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023651/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00096 (3 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely benign reviewed by expert panel P:1 U:1 B:21 O:2
• Conservation: PhyloP100: -2.23
• Publications: 14 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000527.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.2231G>A	p.Arg744Gln	missense	Exon 15 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.2231G>A	p.Arg744Gln	missense	Exon 15 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.2108G>A	p.Arg703Gln	missense	Exon 14 of 17	NP_001182728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.2231G>A	p.Arg744Gln	missense	Exon 15 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.2489G>A	p.Arg830Gln	missense	Exon 15 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.2231G>A	p.Arg744Gln	missense	Exon 15 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes AF: 0.000664 AC: 101 AN: 152084 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000853

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000882

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000855 AC: 215 AN: 251340 AF XY: 0.000942

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00219

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00116

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000959 AC: 1402 AN: 1461766 Hom.: 3 Cov.: 31 AF XY: 0.000942 AC XY: 685 AN XY: 727196

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.000358 AC: 16 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00218 AC: 57 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000916 AC: 79 AN: 86256

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53374

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00107 AC: 1188 AN: 1111954

Other (OTH) AF: 0.000762 AC: 46 AN: 60388

GnomAD4 genome AF: 0.000664 AC: 101 AN: 152200 Hom.: 0 Cov.: 30 AF XY: 0.000591 AC XY: 44 AN XY: 74414

African (AFR) AF: 0.000217 AC: 9 AN: 41538

American (AMR) AF: 0.000852 AC: 13 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4820

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000882 AC: 60 AN: 68002

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000985 Hom.: 2

Bravo AF: 0.000654

ExAC AF: 0.000815 AC: 99

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00142

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1 Uncertain:1 Benign:21 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:1 Uncertain:1 Benign:11

Jul 30, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 26, 2025

Department of Genetics of Metabolic Diseases, Institute of Medical & Molecular Genetics, Hospital Universitario Hospital La Paz

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing;in vitro

The NM_000527.5(LDLR): c.2231G>A (p.Arg744Gln) variant is classified as likely benign for familial hypercholesterolemia according to the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines. In silico analysis predicted a benign effect (BP4). The variant was detected in the patient in combination with another pathogenic variant (BP2). Functional studies demonstrated LDLR expression and activity levels comparable to the wild type, with 85% LDL uptake and 80% binding efficiency relative to wild type.

Institute for Integrative and Experimental Genomics, University of Luebeck

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: research

May 27, 2022

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000527.5(LDLR): c.2231G>A (p.Arg744Gln) variant is classified as Likely benign for Familial Hypercholesterolemia by applying evidence codes BP4, BP2 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: BP4 - REVEL score is 0.291. It is below 0.5, so splicing evaluation is required. Functional data on splicing is not available. A) Variant not on limits. B) Variant is exonic and within range, but it does not create a de novo AG or GT site. The variant is not predicted to alter splicing. BP2 - 2 individuals from Ambry Genetics: Patient 1 has LDLR p.Gln33* in trans. Phenotype LDL 111 mg/dl (on treatment); Patient 2 has LDLR p.Gly373Asp in trans. Phenotype = "high chol". PS3_supporting - level 3 assay (PMID: 9409298) - Heterozygous patients' lymphoblasts, immunoblotting, I125-LDL assay: no precursor detectable, degradation of 125I-LDL = 73%. Variant has 2 Supporting evidence codes towards Benign, enough to classify as Likely benign, and only 1 Supporting evidence code towards Pathogenic. The Benign criteria overwhelms the Pathogenic criteria, so we are confident in classifying this variant as Likely benign.

Mar 30, 2017

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 23, 2017

Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: literature only

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: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

subjects mutated among 2600 FH index cases screened = 7 / previously described in association with FH/Software predictions: Benign

Aug 31, 2016

Cardiovascular Biomarker Research Laboratory, Mayo Clinic

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

MAF =<0.3%.

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

Dec 31, 2023

Institute of Human Genetics, University Hospital Muenster

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: BP1,BP4

not provided Benign:6 Other:2

SNPedia

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Dept. of Genetics and Pharmacogenomics, Merck Research Labs

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LDLR: BP4, BS1

Jun 18, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 01, 2017

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: The LDLR c.2231G>A (p.Arg744Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is located outside of any known functional domain or repeat. 4/4 in silico tools predict benign outcome for this variant (SNP&GO was not used due to a low reliability index), however no experimental studies were published at the time of evaluation (ACMG BP4). The variant of interest has been identified in a large, broad control datasets of ExAC at a frequency of 0.0008 (99/121250 chrs tested), reaching the 0.0011 in several sub-populations (South Asians and European NF) including 1 homozygote. Although the observed frequency is similar to the estimated maximal expected allele frequency of a pathogenic LDLR variant (~0.001), thus supporting benign interpretation, the information on lipid profiling in these individuals is not available for individual review. The variant of interest was reported in multiple patients with elevated cholesterol level, including patient(s) carrying a known pathogenic variant APOB p.R3500Q (ACMG BP5), in whom lipid profiling results were not significantly different from data observed in patients carrying APOB R3500Q alone (Brusgaard, 2006) (ACMG BP5). In addition, per Dutch FH-database, cholesterol levels of R723Q positive and R723Q negative relatives are virtually similar (ACMG BS4), again favoring benign classification. The c.2231G>A was identified heterozygously in a healthy Caucasian adult undergoing carrier screening (ACMG BS2). Lastly, multiple clinical diagnostic laboratories/reputable databases classified this variant as Benign/Likely Benign (ACMG BP6). Considering all evidence the variant was conservatively classified as Likely Benign until additional evidence supporting its presence in normolipedimic control subjects is obtained.ACMG Classification: BRationale for Pathogenicity: none. Rationale for being Benign: BS2, BS4, BP4, BP5; BP6 was not engaged due to discordant classifications.

Dec 23, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Familial hypercholesterolemia Benign:2

Sep 16, 2020

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 02, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Cardiovascular phenotype Benign:1

Apr 13, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	0.042
DANN	Benign	0.70
DEOGEN2	Benign	0.36	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.42	T
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.0	N
PhyloP100		-2.2
PrimateAI	Benign	0.17	T
PROVEAN	Benign	-0.43	N
REVEL	Uncertain	0.29
Sift	Benign	0.60	T
Sift4G	Benign	0.48	T
Polyphen		0.0010	B
Vest4		0.037
MVP		0.97
MPC		0.24
ClinPred		0.0012	T
GERP RS		-6.8
Varity_R		0.017
gMVP		0.60
Mutation Taster		=80/20	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs137853963; hg19: chr19-11233940;