rs5928

Positions:

chr19-11129564-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. BS1PP3PS3

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.2441G>A (p.Arg814Gln) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes BS1, PS3 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 30 August 2024. The supporting evidence is as follows: BS1: FAF=0.003604 (0.3604%) in African/African American exomes + genomes (gnomAD v4.1.0). PP3: REVEL=0.768.PS3: Level 1 assay, PMID 37739193 (Mori et al., 2024): Heterologous cells (HepG2 transfected cells with CRISPR/Cas9), FACS, WB, and CLSM assays. FACS: ~40% cell surface LDLR, 6% binding, and 7% uptake; WB: altered expression of LDLR in HepG2 cells transfected ---- results are below 70% of wild-type, consistent with damaging effect. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023671/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.0011 ( 2 hom., cov: 31)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:2U:7B:8O:1

Conservation

PhyloP100: 4.12

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.

PS3

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

PP3

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

BS1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.2441G>A	p.Arg814Gln	missense_variant	17/18	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.2441G>A	p.Arg814Gln	missense_variant	17/18	1	NM_000527.5	ENSP00000454071	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.00111

AC:

168

AN:

151912

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00384

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000526

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000259

AC:

AN:

251446

Hom.:

AF XY:

0.000162

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.00351

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000121

AC:

177

AN:

1461820

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.00412

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.000364

GnomAD4 genome

AF:

0.00111

AC:

169

AN:

152030

Hom.:

Cov.:

AF XY:

0.00104

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.00386

Gnomad4 AMR

AF:

0.000525

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000242

Hom.:

Bravo

AF:

0.00142

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000280

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:7Benign:8Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:2Uncertain:3Benign:2

Likely pathogenic, 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.2441G>A (also known as p.Arg793Gln in the mature protein), replaces an arginine with glutamine at codon 814 of the LDLR protein (p.Arg814Gln). 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 classified as “Likely Pathogenic” from evidence as follows. It is located within a highly conserved functional domain (Cytoplasmic domain) essential for LDLR internalization. This variant was historically assessed in-vivo (PM3) and in-vitro in homozygous FH (PS3-moderate), observed as a founder mutation for FH (PS4) or a polymorphism at risk of hypercholesterolemia in populations of African ancestry, and was estimated as pathogenic in-silico (REVEL= 0,768) by disrupting a domain required for MYLIP-triggered down-regulation of LDLR (PP3). However, discrepant observations in mildly hypercholesterolemic or normolipidemic subjects, a high frequency in the general population (GnomAD= 0.00111, with no homozygotes) and lack of high-level in-vitro functional studies lead to classify this variant as “Likely Pathogenic” with low penetrance. -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Jul 02, 2021	The c.2441G>A (p.Arg814Gln) variant identified in the LDLR gene substitutes a moderately conserved Arginine for Glutamine at amino acid 814/861(exon 17/18). This variant is found with appreciable frequency in gnomAD(v3.1.1), including in two homozygotes (168 heterozygotes, 2 homozygotes; allele frequency:1.11e-3), which is higher than expected for a pathogenic variant in the LDLR gene. The c.2441G>A (p.Arg814Gln) variant is reported in ClinVar as Pathogenic, Likely Pathogenic, Likely Benign, and as a Variant of Uncertain Significance (VarID:161278). This variant has been identified in many affected individuals in the literature, although its role in relation to hyperlipidemia in those individuals is not clearly defined [PMID:9544746, 10882754, 16389549, 27784735, 33508743]. In silico algorithms predict this variant to be Damaging (SIFT; score:0.00) and Pathogenic (REVEL; score:0.768) to the function of the canonical transcript. While the c.2441G>A(p.Arg814Gln) variant identified in the LDLR gene has been identified in many affected individuals in the literature and is predicted damaging by in silico predictors, its allele frequency is higher than expected. Given the conflicting evidence regarding its pathogenicity, the c.2441G>A (p.Arg814Gln) variant identified in the LDLR gene is reported as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Likely benign, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
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 = 3 , family member = 1/previously described in association with FH/Software predictions: Conflicting -
Uncertain significance, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Aug 30, 2024	The NM_000527.5(LDLR):c.2441G>A (p.Arg814Gln) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes BS1, PS3 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 30 August 2024. The supporting evidence is as follows: BS1: FAF=0.003604 (0.3604%) in African/African American exomes + genomes (gnomAD v4.1.0). PP3: REVEL=0.768. PS3: Level 1 assay, PMID 37739193 (Mori et al., 2024): Heterologous cells (HepG2 transfected cells with CRISPR/Cas9), FACS, WB, and CLSM assays. FACS: ~40% cell surface LDLR, 6% binding, and 7% uptake; WB: altered expression of LDLR in HepG2 cells transfected ---- results are below 70% of wild-type, consistent with damaging effect. -

not provided

Uncertain:3Benign:1Other:1

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The LDLR p.Arg646Gln variant was identified in 4 of 1430 proband chromosomes (frequency: 0.0028) from individuals or families with familial hypercholesterolemia (FH) or high LDL-C (Humphries_2006_PMID:16389549; Thiart_2000_PMID:10882754; Santos_2014_PMID:24529145; Lange_2014_PMID:24507775). The variant was also identified in dbSNP (ID: rs5928), LOVD 3.0 and ClinVar (classified as likely benign by 4 submitters, as a VUS by 3 submitters, as likely pathogenic by 1 submitter and as pathogenic by 1 submitter). The variant was identified in control databases in 101 of 282836 chromosomes at a frequency of 0.000357 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 93 of 24970 chromosomes (freq: 0.003724), Other in 1 of 7224 chromosomes (freq: 0.000138), Latino in 4 of 35440 chromosomes (freq: 0.000113), South Asian in 1 of 30614 chromosomes (freq: 0.000033) and European (non-Finnish) in 2 of 129174 chromosomes (freq: 0.000015), while the variant was not observed in the Ashkenazi Jewish, East Asian or European (Finnish) populations. The p.Arg646 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	LDLR: BS1, BS2 -
not provided, no classification provided	in vitro	Dept. of Genetics and Pharmacogenomics, Merck Research Labs	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2022	Identified in individuals with confirmed or suspected familial hypercholesterolemia (FH) (Arca et al., 1998; Vergotine et al., 2001; Fouchier et al., 2005; Humphries et al., 2006; Lange et al., 2014; Santos et al., 2014; Sanchez-Hernandez et al., 2016; Martin-Campos et al., 2018; Futema et al., 2021), familial combined hyperlipidemia (Minicocci et al., 2015), coronary heart disease (Thiart et al., 2000), and/or a history of early myocardial infarction (Do et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate conflicting results with some studies showing significantly lower fractional catabolic rate which suggests reduced in vivo LDL receptor activity (Arca et al., 1998), while other studies show LDL uptake is similar to wild type suggesting no functional impact (Thormaehlen et al., 2015); Also known as R793Q; This variant is associated with the following publications: (PMID: 26332594, 35047021, 24055113, 25637381, 25487149, 10882754, 24507775, 16250003, 16389549, 24529145, 25647241, 32906206, 11845603, 26342331, 27784735, 30293936, 33508743, 9544746, 32719484) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 21, 2023	In the published literature, this variant has been reported in several individuals affected with hypercholesterolemia (PMIDs: 10882754 (2000), 11845603 (2001), 16250003 (2005), 16389549 (2006), 24529145 (2014), 26802169 (2016), 28220743 (2017), 30293936 (2018), 34040191 (2021), 35047021 (2021), 36769678 (2023)). In addition, this variant was also reported to occur with other variants in affected individuals (PMIDs: 27784735 (2016), 34496902 (2021)). Functional studies of this variant reported reduced LDLR degradation (PMID: 9544746 (1998)) and that the variant did not disrupt LDL uptake activity (PMID: 25647241 (2015)), however, further research is needed. The frequency of this variant in the general population, 0.0037 (93/24970 chromosomes in African/African American 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. -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 15, 2024	Variant summary: LDLR c.2441G>A (p.Arg814Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00026 in 251604 control chromosomes, predominantly at a frequency of 0.0035 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in LDLR causing Early Onset Coronary Artery Disease phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.2441G>A has been reported in the literature in individuals affected with hypercholesterolemia without strong evidence for causality (e.g. Arca_1997, Thiart_2000, Vergotine_2001, Humphries_2006, Sanchez-Hernandez_2016, Futema_2021, DErasmo_2021, Rimbert_2022). These reports do not provide unequivocal conclusions about association of the variant with Early Onset Coronary Artery Disease. One co-occurrence with another pathogenic variants has been reported (LDLR c.2389G>A, p.Val797Met), providing supporting evidence for a benign role. At least one publication reports a modest reduction of LDL-R activity in-vivo in a patient with the variant (e.g. Arca_1997). The following publications have been ascertained in the context of this evaluation (PMID: 16389549, 10882754, 16250003, 11845603, 24055113, 25637381, 8295321, 24529145, 26802169, 27784735, 30293936, 33508743, 34496902, 35047021).ClinVar contains an entry for this variant (Variation ID: 161278). Based on the evidence outlined above, the variant was classified as likely benign. -

Familial hypercholesterolemia

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 23, 2020	- -

Hypercholesterolemia

Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 19, 2022

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.036

BayesDel_noAF

Pathogenic

0.24

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.33

M_CAP

Pathogenic

0.74

MetaRNN

Benign

0.089

MutationTaster

Benign

1.0

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

PROVEAN

Benign

1.1

Sift

Pathogenic

0.0

Sift4G

Benign

0.17

Vest4

0.79

MVP

1.0

ClinPred

0.027

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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