rs200727689

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000527.5(LDLR):c.502G>A(p.Asp168Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,613,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D168E) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21O:1

Conservation

PhyloP100: 9.87

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 Pathogenic. Variant got 18 ACMG points.

PM1

In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000527.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-11105409-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 375785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.944

PP5

Variant 19-11105408-G-A is Pathogenic according to our data. Variant chr19-11105408-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 183136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11105408-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.502G>A	p.Asp168Asn	missense_variant	4/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.502G>A	p.Asp168Asn	missense_variant	4/18	1	NM_000527.5	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152226

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251288

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135884

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000390

AC:

AN:

1461684

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

727148

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000486

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

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:

0.000239

Hom.:

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:21Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:12

Pathogenic, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Apr 04, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 06, 2021	- -
Pathogenic, criteria provided, single submitter	research	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	Mar 10, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 09, 2023	- -
Likely pathogenic, 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 with co-segregation / FH-Sephardic, 2 to 5% LDLR Activity / Software predictions: Conflicting -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Aug 24, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 05, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	This missense variant (also known as p.Asp147Asn in the mature protein) replaces aspartic acid with asparagine at codon 168 in the fourth LDLR type A repeat 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). Functional studies have shown that this variant causes a significant decrease in LDL binding and uptake, although effect is not as severe as null alleles (PMID: 25545329, 25647241). This variant has been reported in over ten individuals and families affected with familial hypercholesterolemia (PMID: 15556094, 16205024, 16389549, 17955342, 22859806, 23669246, 27784735, 28379029, 33807407, 34037665; Color internal data), including a homozygous individual with severe phenotype (PMID: 27784735). This variant has been identified in 2/251288 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same amino acid position (p.Asp168His, p.Asp168Gly, p.Asp168Tyr) are known to be disease-causing (ClinVar variation ID: 251258, 251260, 251259), indicating that aspartic acid at this position is important for LDLR function. Based on available evidence, this variant is classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Nov 05, 2016	- -
Likely pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	-	The LDLR c.502G>A (p.D168N) variant has been previously reported in the heterozygous state in autosomal dominant familial hypercholesterolemia (PMID: 9259195; 9678702; 12124988; 15556094; 19007590; 25545329; 25647241). -

Familial hypercholesterolemia

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 02, 2020	Variant summary: LDLR c.502G>A (p.Asp168Asn) results in a conservative amino acid change located in the LDLR ligand binding domain (R4) (Etxebarria_2015) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251288 control chromosomes (gnomAD). c.502G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Taylor_2010, Rall_2014, Sanchez-Hernandez_2016, Wald-2016). These data indicate that the variant is very likely to be associated with disease. At least one functional study reports this variant effect results in an impaired LDL binding capacity of WT. Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (3x) and likely pathogenic (4x). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Feb 04, 2021	The c.502G>A (p.Asp168Asn) variant in the LDLR gene is located on the exon 4 and is predicted to replace aspartic acid with asparagine at codon 168 (p.Asp168Asn). The variant has been reported in more than 10 unrelated individuals affected with familial hypercholesterolemia (PMID: 33807407, 32522009, 27783906, 27784735, 28379029, 22859806, 19007590, 16389549, 16205024, 9678702, 30293936). The p.Asp168Asn variant is located in the well-established functional domain (amino acids 105-232) critical to the protein function. Experimental study in the LDLR deficient cell line proved the negative functional impact of this variant and defective LDL binding (<70%) (PMID: 25545329). The variant has been reported in ClinVar (ID: 183136). This variant is rare in the general population according to gnomAD (2/251288). Computational prediction algorithms suggest a deleterious impact (REVEL score 0.78). Therefore, the c.502G>A (p.Asp168Asn) variant of LDLR has been classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 01, 2023	This missense variant (also known as p.Asp147Asn in the mature protein) replaces aspartic acid with asparagine at codon 168 in the fourth LDLR type A repeat 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). Functional studies have shown that this variant causes a significant decrease in LDL binding and uptake, although effect is not as severe as null alleles (PMID: 25545329, 25647241). This variant has been reported in over ten individuals and families affected with familial hypercholesterolemia (PMID: 15556094, 16205024, 16389549, 17955342, 22859806, 23669246, 27784735, 28379029, 33807407, 34037665; Color internal data), including a homozygous individual with severe phenotype (PMID: 27784735). This variant has been identified in 2/251288 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same amino acid position (p.Asp168His, p.Asp168Gly, p.Asp168Tyr) are known to be disease-causing (ClinVar variation ID: 251258, 251260, 251259), indicating that aspartic acid at this position is important for LDLR function. Based on available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 07, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 168 of the LDLR protein (p.Asp168Asn). This variant is present in population databases (rs200727689, gnomAD 0.002%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9259195, 9678702, 12124988, 15556094, 16205024, 19007590, 22859806, 27784735). This variant is also known as p.Asp147Asn. ClinVar contains an entry for this variant (Variation ID: 183136). 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: 25545329, 25647241). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 11, 2020	- -

not provided

Pathogenic:1Other:1

not provided, no classification provided	in vitro	Dept. of Genetics and Pharmacogenomics, Merck Research Labs	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 10, 2022	Published functional studies demonstrate decreased receptor binding and LDL uptake compared to wild type protein (Etxebarria et al., 2015; Thormaehlen et al., 2015); Not observed at a significant frequency in large population cohorts (gnomAD); Also known as D147N; This variant is associated with the following publications: (PMID: 9259195, 30617148, 15556094, 16205024, 31447099, 25487149, 9678702, 12124988, 19007590, 25647241, 22859806, 27784735, 29874871, 28379029, 23669246, 32522009, 33807407, 32853555, 32719484, 33740630, 34037665, 33087929, 2988123, 12459547, 25545329) -

Homozygous familial hypercholesterolemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 07, 2021

The p.Asp168Asn variant in LDLR has been reported in the heterozygous state in at least 12 individuals (11 heterozygotes, 1 homozygote) with familial hypercholesterolemia (FH), and in 2 individuals with early-onset myocardial infarction and segregated with FH in one affected relative (Day 1997 PMID: 9259195, Lee 1998 PMID: 9678702, Punzalan 2005 PMID: 16205024, Taylor 2010 PMID: 20236128, Do 2015 PMID: 25487149, Wald 2016 PMID: 27783906, Sanchez-Hernandez 2016 PMID: 27784735). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 183136) and has been identified in 0.002% (2/113632) European chromosomes by the gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that the p.Asp168Asn variant may cause a decrease in LDL uptake and binding (Etxebarria 2015 PMID: 25545329) and computational prediction tools and conservation analyses are consistent with pathogenicity. Additionally, other variants at this position (p.Asp168His, p.Asp168Gly, p.Asp168Gln) have been reported in association with FH by multiple clinical laboratories in ClinVar. In summary, the p.Asp168Asn variant meets criteria to be classified as pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PS4, PS3_Moderate, PM1, PM2_Supporting, PP3, PM5_Supporting. -

LDLR-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 13, 2023

The LDLR c.502G>A variant is predicted to result in the amino acid substitution p.Asp168Asn. This variant is alternatively referred to as p.Asp147Asn using Legacy nomenclature. This variant and other similar variants affecting amino acid Asp168 have been reported in several unrelated patients with hypercholesterolemia (Day et al. 1997 PubMed ID: 9259195; Lee et al. 1998 PubMed ID: 9678702; Punzalan et al. 2005 PubMed ID: 16205024; Civiera et al. 2008 PubMed ID: 19007590; Etxebarria et al. 2015 PubMed ID: 25545329). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-11216084-G-A) and is reported as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/183136/). This variant is interpreted as pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 20, 2024

The p.D168N variant (also known as c.502G>A), located in coding exon 4 of the LDLR gene, results from a G to A substitution at nucleotide position 502. The aspartic acid at codon 168 is replaced by asparagine, an amino acid with highly similar properties, and is located in the ligand binding region of the protein. This alteration (also referred to as D147N) has been detected in individuals from multiple familial hypercholesterolemia cohorts and in an an individual with mixed hyperlipidemia (Day IN et al. Hum Mutat. 1997;10:116-27; Lee WK et al. J Med Genet. 1998;35:573-8; Laurie AD et al. Atheroscler Suppl. 2004;5(5):13-5;Civeira F et al. J Am Coll Cardiol. 2008; Futema M et al. Atherosclerosis. 2013;229:161-8; Raal FJ et al. Lancet. 2015;385(9965):341-50; Sánchez-Hernández RM et al. Circ Cardiovasc Genet. 2016;9(6):504-510). This variant has been reported to result in reduced LDL binding and uptake in vitro (Etxebarria A et al. Atherosclerosis. 2015 Feb;238(2):304-12; Thormaehlen AS et al. PLoS Genet. 2015;11(2):e1004855). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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

0.81

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

D;.;.;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Pathogenic

0.70

MetaRNN

Pathogenic

0.94

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.1

M;.;.;M

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-4.5

D;D;D;D

Sift

Uncertain

0.026

D;D;D;D

Sift4G

Uncertain

0.046

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.72

MVP

1.0

MPC

0.80

ClinPred

0.98

GERP RS

5.6

Varity_R

0.89

gMVP

0.99

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