rs375009082

Positions:

chr19-11120480-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP4PS4_SupportingPS3_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

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:5U:5

Conservation

PhyloP100: 9.94

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 Likely_pathogenic. Variant got 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/exons	MANE	Protein	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.2098G>A	p.Asp700Asn	missense_variant	14/18	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.2098G>A	p.Asp700Asn	missense_variant	14/18	1	NM_000527.5	ENSP00000454071	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251024

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135732

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:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000281

AC:

AN:

1461516

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

727084

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000333

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000163

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5Uncertain:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Familial hypercholesterolemia

Pathogenic:3Uncertain:1

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 19, 2022	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 (gnomAD). The variant, c.2098G>A, 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). Seven other submitters, including a variant curation expert panel (ClinGen), have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as VUS (n=5), while ClinGen classified it as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 25, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	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; Invitae). This variant is also known as p.D679N. ClinVar contains an entry for this variant (Variation ID: 200923). 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: 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; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Hypercholesterolemia, familial, 1

Pathogenic:1Uncertain:1

Likely pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Mar 25, 2022	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. -
Uncertain significance, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 29, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 24, 2017	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

Likely pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Nov 17, 2022

The frequency of this variant in the general population, 0.000062 (8/129062 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with familial hypercholesterolemia (PMIDs: 28964736 (2017), 23669246 (2013), 19118540 (2009), and 15199436 (2004)). In addition, a functional study showed significantly reduced low-density lipoprotein uptake in cells with this variant (PMID: 34869944 (2021)). 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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2024

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 alteration (also referred to as p.D679N) has been detected in familial hypercholesterolemia cohorts; however, detail was limited (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). This variant has also been reported as a secondary finding in an exome cohort, and in a population-based cohort (Retterer K et al. Genet. Med. 2016;18:696-704; Abul-Husn NS. Science. 2016;354(6319)). Studies suggest this alteration may have an impact on protein function (Larrea-Sebal A et al. JACC Basic Transl Sci, 2021 Nov;6:815-827). Alterations affecting the same amino acid (p.D700E, c.2100C>G and p.D700G, c.2099A>G) have been reported in patients with familial hypercholesterolemia; although, one was noted to co-segregate with a second LDLR alteration (Cenarro A et al. Hum. Mutat., 1998;11:413; García-García AB et al. Hum. Mutat., 2001;18:458-9). 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

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

D;.;.;.;.

Eigen

Benign

0.18

Eigen_PC

Benign

0.068

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.88

D;D;D;D;D

M_CAP

Pathogenic

0.84

MetaRNN

Pathogenic

0.91

D;D;D;D;D

MetaSVM

Pathogenic

0.94

MutationAssessor

Uncertain

2.3

M;.;.;.;M

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.48

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

GERP RS

4.3

Varity_R

0.43

gMVP

0.88

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