rs375009082

Variant names:

• chr19-11120480-G-A
• rs375009082
• NM_000527.5:c.2098G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11120480-G-A
• chr19-11120480-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP4 PS4_Supporting PS3_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.2098G>A (p.Asp700Asn) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PS3_Moderate, PS4_supporting and PP4 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 = 0.00006199 (0.006199%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1), so PM2 is Met.PS3_Moderate - Level 2 assays: PMID 34869944:Heterologous cells (CHO), FACS assays - result - 20% uptake.---- functional study is consistent with damaging effect, so PS3_Moderate is Met.PS4_supporting - Variant meets PM2 and is identified in 2 unrelated index cases: 1 index case with DLCN>=6 from Color Health, Inc, and 1 index case with Simon Broome criteria (TC of 9.8 mmol/L and personal or family history of CHD) from UK (PMID:23669246), so PS4_Supporting is Met.PP4 - Variant meets PM2 and is identified in 2 unrelated index cases (see PS4 for details), so PP4 is Met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023633/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:7 U:5
• Conservation: PhyloP100: 9.94
• Publications: 8 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_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.
• 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	c.2098G>A	p.Asp700Asn	missense_variant	Exon 14 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.2098G>A	p.Asp700Asn	missense_variant	Exon 14 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251024 AF XY: 0.0000147

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: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000281 AC: 41 AN: 1461516 Hom.: 0 Cov.: 35 AF XY: 0.0000275 AC XY: 20 AN XY: 727084

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53046

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000333 AC: 37 AN: 1112010

Other (OTH) AF: 0.0000497 AC: 3 AN: 60394

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74326

African (AFR) AF: 0.0000241 AC: 1 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000447 Hom.: 0

Bravo AF: 0.0000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7 Uncertain:5

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:3 Uncertain:1

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Sep 18, 2024

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.Asp679Asn in the mature protein) replaces aspartic acid with asparagine at codon 700 in the EGF precursor homology domain of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant causes a significant decrease in LDLR uptake (PMID: 34869944). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 15199436, 23669246, 28008010; Color internal data). This variant has been identified in 8/282422 chromosomes in the general population by the Genome Aggregation Database (gnomAD). This variant is classified as likely pathogenic by the ClinGen Familial Hypercholesterolemia VCEP (ClinVar variation ID: 200923). Additionally, a different variant occurring at the same codon, p.Asp700Gly, is considered to be disease-causing (Clinvar variation ID: 252220), indicating that aspartic acid at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -

Mar 25, 2022

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.2098G>A (p.Asp700Asn) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PS3_Moderate, PS4_supporting and PP4 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 = 0.00006199 (0.006199%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1), so PM2 is Met. PS3_Moderate - Level 2 assays: PMID 34869944: Heterologous cells (CHO), FACS assays - result - 20% uptake. ---- functional study is consistent with damaging effect, so PS3_Moderate is Met. PS4_supporting - Variant meets PM2 and is identified in 2 unrelated index cases: 1 index case with DLCN>=6 from Color Health, Inc, and 1 index case with Simon Broome criteria (TC of 9.8 mmol/L and personal or family history of CHD) from UK (PMID: 23669246), so PS4_Supporting is Met. PP4 - Variant meets PM2 and is identified in 2 unrelated index cases (see PS4 for details), so PP4 is Met. -

Jan 29, 2024

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LDLR c.2098G>A p.(Asp700Asn) missense variant, also known as p.D679N, has been identified in individuals with familial hypercholesterolemia (PMID: 15199436; 23669246; 28964736). Additionally, a different amino acid substitution at the same codon has been reported in individuals with familial hypercholesterolemia. A functional study conducted in non-human cells demonstrated that this variant reduces LDL receptor activity (PMID: 34869944). This variant was not observed at a significant frequency in version 2.1.1 or version 4.0.0 of the Genome Aggregation Database. Based on the available evidence, the c.2098G>A p.(Asp700Asn) variant is classified as likely pathogenic for familial hypercholesterolemia. -

Familial hypercholesterolemia Pathogenic:3 Uncertain:1

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 08, 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 700 of the LDLR protein (p.Asp700Asn). This variant is present in population databases (rs375009082, gnomAD 0.007%). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 15199436, 19118540, 23669246; internal data). 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.D679N. ClinVar contains an entry for this variant (Variation ID: 200923). 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: 34869944). This variant disrupts the p.Asn700 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 22353362, 32015373, 34456049; internal data), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Jul 26, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces aspartic acid with asparagine at codon 700 in the EGF precursor homology domain of the LDLR protein. This variant is also known as p.Asp679Asn in the mature protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. Functional studies have shown that this variant causes a significant decrease in LDLR uptake (PMID: 34869944). This variant has been reported in at least eight individuals affected with familial hypercholesterolemia (PMID: 15199436, 23669246, 28008010; Color internal data). This variant has been identified in 8/282422 chromosomes in the general population by the Genome Aggregation Database (gnomAD). This variant is classified as likely pathogenic by the ClinGen Familial Hypercholesterolemia VCEP (ClinVar variation ID: 200923). Additionally, a different variant occurring at the same codon, p.Asp700Gly, is considered to be disease-causing (Clinvar variation ID: 252220), indicating that aspartic acid at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -

Apr 11, 2025

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LDLR c.2098G>A (p.Asp700Asn) results in a conservative amino acid change located in the EGF-like domain (IPR000742) of 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 2e-05 in 251024 control chromosomes. has been reported in the literature in multiple individuals affected with (familial) hypercholesterolemia (e.g. Leren_2004, Laurie_2009, Futema_2013, Defesche_2017, Trinder_2020, Dron_2020), however, it was also found in controls (Do_2015, Narang_2020). These data indicate that the variant maybe associated with disease. A recent publication reported experimental evidence evaluating an impact on protein function, and demonstrated a decreased LDLR activity (~20% of normal) in an in vitro expression system (Larrea-Sebal_2021). The following publications have been ascertained in the context of this evaluation (PMID: 28964736, 25487149, 32041611, 23669246, 34869944, 19118540, 15199436, 32906206, 32466883). ClinVar contains an entry for this variant (Variation ID: 200923). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not specified Uncertain:2

Dec 29, 2016

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 24, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in 2 publications: one describing a method for detecting variants in individuals heterozygous for LDLR variants (no phenotype information) and one where it was found in a control subject. The variant is classified in ClinVar as VUS by GeneDx and British Heart Foundation. The variant is present in ExAC with a Max MAF of 0.006% (4 European alleles). -

not provided Pathogenic:1

Nov 07, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LDLR c.2098G>A (p.Asp700Asn) variant has been reported in the published literature in multiple individuals with familial hypercholesterolemia (PMIDs: 28964736 (2017), 23669246 (2013), 19118540 (2009), 15199436 (2004)), and shown to cause significantly reduced cellular LDL uptake in vivo (PMID: 34869944 (2021)). The frequency of this variant in the general population, 0.000062 (8/129062 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. -

Cardiovascular phenotype Uncertain:1

Mar 03, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D700N variant (also known as c.2098G>A), located in coding exon 14 of the LDLR gene, results from a G to A substitution at nucleotide position 2098. The aspartic acid at codon 700 is replaced by asparagine, an amino acid with highly similar properties. This variant (also referred to as p.D679N) was reported in individual(s) with features consistent with familial hypercholesterolemia (Leren TP et al. Semin Vasc Med, 2004;4:75-85; Futema M et al. Atherosclerosis, 2013;229:161-8; Defesche JC et al. J Clin Lipidol. 2017;11(6):1338-1346.e7; external communication, Ambry internal data). In an assay testing LDLR function, this variant showed a functionally abnormal result (Larrea-Sebal A et al. JACC Basic Transl Sci, 2021 Nov;6:815-827). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;.;.;.;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.068
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.88	D;D;D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Uncertain	2.3	M;.;.;.;M
PhyloP100		9.9
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-3.7	D;D;D;D;D
REVEL	Pathogenic	0.68
Sift	Benign	0.19	T;T;T;T;T
Sift4G	Benign	0.17	T;T;T;T;T
Polyphen		1.0	D;.;.;.;.
Vest4		0.73
MVP		1.0
MPC		0.80
ClinPred		0.54	D
GERP RS		4.3
Varity_R		0.43
gMVP		0.88
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs375009082; hg19: chr19-11231156;