NM_000527.5:c.502G>A

Variant names:

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:23O: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 disulfide_bond (size 17) in uniprot entity LDLR_HUMAN there are 50 pathogenic changes around while only 1 benign (98%) 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 chr19-11105410-C-A is described in Lovd as [Likely_pathogenic].

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 rank	MANE	Protein	UniProt
LDLR	NM_000527.5 link	c.502G>A	p.Asp168Asn	missense_variant	Exon 4 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.502G>A	p.Asp168Asn	missense_variant	Exon 4 of 18	1	NM_000527.5	ENSP00000454071.1		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:23Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:13

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

- -

Mar 01, 2016

Fundacion Hipercolesterolemia Familiar

Significance: Pathogenic

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

- -

Oct 09, 2023

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS3_Moderate+PS4+PM5 -

Dec 06, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 12, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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 = 3 , family member = 1 with co-segregation / FH-Sephardic, 2 to 5% LDLR Activity / Software predictions: Conflicting -

Apr 04, 2014

Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 05, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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). -

Aug 24, 2021

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 10, 2019

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Familial hypercholesterolemia

Pathogenic:6

Oct 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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.Asp147Asn. ClinVar contains an entry for this variant (Variation ID: 183136). 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%. Experimental studies have shown that this missense change affects LDLR function (PMID: 25545329, 25647241). For these reasons, this variant has been classified as Pathogenic. -

Aug 05, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in LDLR is predicted to replace aspartic acid with asparagine at codon 168, p.(Asp168Asn). This variant is also known as p.(Asp147Asn) in the literature. The aspartic acid residue is highly conserved (100 vertebrates, Multiz Alignments), and is located in the LDL-receptor class A domain 4 in exon 4 (amino acids 105-232) which is defined as a mutational hotspot (PMID: 34906454). There is a small physicochemical difference between aspartic acid and asparagine. The highest population minor allele frequency in the population database gnomAD v4.1 is 0.005% (55/1,180,018 alleles) in the European (non-Finnish) population, consistent with familial hypercholersterolaemia (FH). This variant has been reported in at least six unrelated probands with a clinical diagnosis of FH (PMID: 20236128, 30293936, 9678702, 28379029, 15556094). A functional study with limited validation assaying the binding and uptake capabilities of the LDL protein is supportive of a damaging effect on protein function (PMID: 25545329). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.78). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.0, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM1, PM2_Supporting, PP3, PS3_Supporting, PS4_Moderate -

Mar 02, 2020

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 11, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 04, 2021

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 01, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided

Pathogenic:1Other:1

Aug 10, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Dept. of Genetics and Pharmacogenomics, Merck Research Labs

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

Homozygous familial hypercholesterolemia

Pathogenic:1

Apr 07, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 23, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 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

Feb 20, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-4.5

D;D;D;D

REVEL

Pathogenic

0.78

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