rs139624145

chr19-11113620-G-Achr19-11113620-G-Cchr19-11113620-G-T

Variant summary

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

The NM_000527.5(LDLR):c.1444G>A(p.Asp482Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000731 in 1,613,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. D482G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000077 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:27U:1O:1

Conservation

PhyloP100: 8.03

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 2 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 chr19-11113621-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.968

PP5

Variant 19-11113620-G-A is Pathogenic according to our data. Variant chr19-11113620-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 161284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11113620-G-A is described in Lovd as [Pathogenic]. Variant chr19-11113620-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.1444G>A	p.Asp482Asn	missense_variant	10/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.1444G>A	p.Asp482Asn	missense_variant	10/18	1	NM_000527.5	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251310

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135854

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:

0.0000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000766

AC:

112

AN:

1461742

Hom.:

Cov.:

AF XY:

0.0000660

AC XY:

AN XY:

727178

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.0000989

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000446

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:27Uncertain:1Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:18

Likely pathogenic, criteria provided, single submitter	research	Iberoamerican FH Network	Mar 01, 2016	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Asp482Asn (sometimes called p.Asp461Asn) variant in LDLR has been reported in at least 24 individuals (including 4 Czech, 3 German, 1 Norwegian, 1 Italian, and 1 Dutch individuals) with Familial Hypercholesterolemia, segregated with disease in 5 affected relatives from 2 families (PMID: 26036859, 22698793, 9026534, 15199436, 11857755, 16159606, 21310417, 11139254, 11810272), and has been identified in 0.008526% (11/129018) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs139624145). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported as a VUS, a likely pathogenic variant, and a pathogenic variant in ClinVar (Variation ID: 161284). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS4, PP1_Moderate, PP3 (Richards 2015). -
Likely 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	Jul 22, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 11, 2017	Across a selection of the available literature, the LDLR c.1444G>A (p.Asp482Asn) variant has been identified in a heterozygous state in 36 cases with familial hypercholesterolemia (Taylor et al. 2010; Martin et al. 2016; Braenne et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.000087 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence, the p.Asp482Asn variant is classified as pathogenic for familial hypercholesterolemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 08, 2024	This missense variant (also known as p.Asp461Asn in the mature protein) replaces aspartic acid with asparagine at codon 482 in the LDLR type B repeat 2 of the EGF precursor homology domain of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This LDLR variant has been reported in over 40 heterozygous individuals affected with familial hypercholesterolemia (PMID: 8535447, 10559517, 15523646, 16389549, 21310417, 20236128, 23375686, 33740630, 34037665; Color internal data) and is a recurrent variant among Irish individuals affected with familial hypercholesterolemia (PMID: 15523646). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in two individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 30270091). It has been shown that this variant segregates with disease in three affected individuals in one family (PMID: 8535447). This variant has been identified in 11/282680 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon (p.Asp482Tyr, p.Asp482His and p.Asp482Gly), are considered to be disease-causing (ClinVar variation ID: 251845, 251844 and 251846), suggesting that aspartic acid at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	May 11, 2017	The c.1444G>A (p.Asp482Asn) variant in the LDLR gene has been reported in patients with hypercholesterolemia [PMID 8535447, 23375686, 20236128, 16159606, 21326404; legacy name 461]. This variant was observed in five heterozygous individuals in the ExAC population database (http://exac.broadinstitute.org/variant/19-11224296-G-A). Aspartate at position 482 of the LDLR protein is conserved in mammals and while not clinically validated, computer-based algorithms (SIFT and Polyphen-2) predict this p.Asp482Asn change to be deleterious. This c.1444G>A (p.Asp482Asn) variant is thus classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 17, 2022	- -
Likely pathogenic, criteria provided, single submitter	research	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	May 11, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Oct 16, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Nov 05, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 28, 2022	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, criteria provided, single submitter	research	Institute for Integrative and Experimental Genomics, University of Luebeck	-	- -

Familial hypercholesterolemia

Pathogenic:4Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Pathogenic and reported on 09-10-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 05, 2018	Variant summary: LDLR c.1444G>A (p.Asp482Asn) results in a conservative amino acid change located in the LDLR class B repeat 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 4e-05 in 277372 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (4e-05 vs 0.0013), allowing no conclusion about variant significance. c.1444G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Bochmann_2001, Bunn_2002, Fouchier_2001, Graham_1999, Graham_2005, Martin_2016, Ward_1995). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 482 of the LDLR protein (p.Asp482Asn). This variant is present in population databases (rs139624145, gnomAD 0.009%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 8535447, 16389549, 20236128, 21310417, 23375686). This variant is also known as p.Asp461Asn. ClinVar contains an entry for this variant (Variation ID: 161284). 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%. This variant disrupts the p.Asp482 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16389549, 20236128, 21310417). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 07, 2023	This missense variant (also known as p.Asp461Asn in the mature protein) replaces aspartic acid with asparagine at codon 482 in the LDLR type B repeat 2 of the EGF precursor homology domain of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This LDLR variant has been reported in over 40 heterozygous individuals affected with familial hypercholesterolemia (PMID: 8535447, 10559517, 15523646, 16389549, 21310417, 20236128, 23375686, 33740630, 34037665; Color internal data) and is a recurrent variant among Irish individuals affected with familial hypercholesterolemia (PMID: 15523646). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in two individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 30270091). It has been shown that this variant segregates with disease in three affected individuals in one family (PMID: 8535447). This variant has been identified in 11/282680 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon (p.Asp482Tyr, p.Asp482His and p.Asp482Gly), are considered to be disease-causing (ClinVar variation ID: 251845, 251844 and 251846), suggesting that aspartic acid at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 08, 2022	PP1, PP3, PM2_supporting, PM3, PM5, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2023	Functional studies showed that D482N, when present in the homozygous or compound heterozygous state, results in decreased LDL receptor activity (Webb et al., 1996); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as D461N; This variant is associated with the following publications: (PMID: 11810272, 18700895, 25487149, 15556094, 20236128, 22883975, 29874871, 34662886, 25637381, 9026534, 8535447, 11857755, 11139254, 15199436, 21310417, 27680772, 15523646, 25682026, 16159606, 22698793, 23375686, 26036859, 27765764, 23680767, 29284604, 24507775, 31447099, 32220565, 35177841, 32719484, 32041611, 33303402, 33740630, 34037665) -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jan 05, 2022	- -

Hypercholesterolemia

Pathogenic:1Uncertain:1

Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Dec 03, 2018	- -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 26, 2023

The p.D482N variant (also known as c.1444G>A), located in coding exon 10 of the LDLR gene, results from a G to A substitution at nucleotide position 1444. The aspartic acid at codon 482 is replaced by asparagine, an amino acid with highly similar properties. This alteration (also described as legacy p.D461N) has been identified in multiple individuals with familial hypercholesterolemia (FH) (Brænne I et al. Eur. J. Hum. Genet., 2016 Feb;24:191-7; Webb JC et al. J. Lipid Res., 1996 Feb;37:368-81; Ward AJ et al. Hum. Mutat., 1995;6:254-6; Bochmann H et al. Hum. Mutat., 2001;17:76-7; Taylor A et al. Clin. Genet., 2010 Jun;77:572-80; Wang J et al. Arterioscler. Thromb. Vasc. Biol., 2016 12;36:2439-2445; Laurie AD et al. Atheroscler Suppl, 2004 Dec;5:13-5; Ho CK et al. Scott Med J, 2012 Aug;57:148-51; Hooper AJ et al. Atherosclerosis, 2012 Oct;224:430-4). It has been reported to co-segregate with disease in one family (Brænne I et al. Eur J Hum Genet. 2016;24(2):191-7). One study has demonstrated <2% of normal LDL-R activity in an individual with this alteration and a 21 base pair deletion in exon 4 of LDLR (Webb JC et al. J Lipid Res. 1996;37(2):368-81). Another study has reported the p.D482N variant and a second LDLR variant (p.D266E, c.798T>A) in an individual with coronary heart disease (Bochmann H et al. Hum. Mutat., 2001;17:76-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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

0.97

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.20

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

D;.;.;.;.;.

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D;D;D;D;D

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.8

H;.;.;.;.;H

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-4.7

D;D;D;D;D;D

Sift

Pathogenic

0.0

D;D;D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.86

MVP

1.0

MPC

0.80

ClinPred

0.99

GERP RS

4.7

Varity_R

0.97

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