19-11105326-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PS1PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000527.5(LDLR):c.420G>C(p.Glu140Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E140K) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 2.05

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 22 ACMG points.

PS1

Transcript NM_000527.5 (LDLR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd

PM1

In a turn (size 4) in uniprot entity LDLR_HUMAN there are 15 pathogenic changes around while only 0 benign (100%) 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 chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

PP5

Variant 19-11105326-G-C is Pathogenic according to our data. Variant chr19-11105326-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11105326-G-C 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.420G>C	p.Glu140Asp	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.420G>C	p.Glu140Asp	missense_variant	Exon 4 of 18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:7

Jun 05, 2019

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

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

- -

Feb 11, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2017

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This c.420G>C (p.Glu140Asp) variant in the LDLR gene has been reported in multiple individuals with familial hypercholesterolemia (PMID: 11754108, 20145306, 22698793, 23680767). A different variant at the same residue (p.Glu140Lys) has also been described in multiple individuals with familial hypercholesterolemia (PMID: 1301956, 11668627, 21722902, 23375686) The p.Glu140Asp variant occurs within the low-density lipoprotein receptor repeat class A domain of the LDLR protein (https://www.ncbi.nlm.nih.gov/Structure/cdd/wrpsb.cgi?seqinput=NP_001182729.1 ). The c.420G>C variant is not detected in the general population and glutamate at position 140 of the LDLR protein is highly evolutionarily conserved. The c.420G>C (p.Glu140Asp) variant in the LDLR gene is classified as likely pathogenic. -

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

- -

Familial hypercholesterolemia

Pathogenic:3

Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 140 of the LDLR protein (p.Glu140Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypercholesterolemia (PMID: 11754108, 17094996, 20145306). 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. ClinVar contains an entry for this variant (Variation ID: 251216). 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%. This variant disrupts the p.Glu140 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301956, 11668627, 21722902, 23375686). 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. -

Dec 27, 2024

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.420G>C (p.Glu140Asp) results in a conservative amino acid change located in the Low-density lipoprotein receptor domain class A (IPR002172) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251168 control chromosomes. c.420G>C has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (e.g. Tichy_2012, Chamara_2010). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.418G>A, p.Glu140Lys), supporting the critical relevance of codon 140 to LDLR protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20145306, 22698793). ClinVar contains an entry for this variant (Variation ID: 251216). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:2

May 24, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as E119D; This variant is associated with the following publications: (PMID: 10081189, 11754108, 31447099, 29261184, 11524740, 17094996, 20145306, 22698793, 34037665, 32770674, 33489595, 33418990, 33740630) -

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LDLR: PS4, PM1, PM2, PM5, PP4 -

Homozygous familial hypercholesterolemia

Pathogenic:1

Apr 23, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Glu140Asp variant in LDLR has been reported in the heterozygous state in at least 10 individuals with familial hypercholesterolemia (FH; Kuhrova 2002, Tosi 2007, Chmara 2010, Tichy 2012, Vandrovcova 2013, Duskova 2011). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 251216) and was absent in large population studies. Computational prediction tools and conservation analysis suggest that the p.Glu140Asp variant may impact the protein. Additionally, different amino acid changes at this position have been reported in individuals with FH (Stenson 2017), including the p.Glu140Lys variant which has been classified as likely pathogenic by other clinical laboratories (ClinVar variation ID 251213), suggesting that changes at this amino acid position are not tolerated. In summary, although additional studies are required to fully establish its clinical significance, the p.Glu140Asp variant is likely pathogenic. ACMG/AMP applied: PS4_Moderate, PM5, PM2, PP3. -

Cardiovascular phenotype

Pathogenic:1

May 28, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E140D pathogenic mutation (also known as c.420G>C), located in coding exon 4 of the LDLR gene, results from a G to C substitution at nucleotide position 420. The glutamic acid at codon 140 is replaced by aspartic acid, an amino acid with highly similar properties. This alteration impacts a residue in the conserved cluster of acidic amino acids at the C-terminal end of LDLR class A repeat 3 (Jeon H and Blacklow C. Annu. Rev. Biochem. 2005;74:535-62). This variant has been reported in multiple individuals with familial hypercholesterolemia (FH) (Tosi I et al. Atherosclerosis, 2007 Sep;194:102-11; Chmara M et al, J. Appl. Genet. 2010 ; 51(1):95-106; Tichý L et al. Atherosclerosis, 2012 Aug;223:401-8). Internal structural analysis indicates that this alteration results in disruption of the structurally critical Ca-binding SDE motif (Fisher C et al. Mol. Cell, 2006 Apr;22:277-83; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

D;.;.;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D;D

M_CAP

Pathogenic

0.84

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.9

H;.;.;H

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.7

D;D;D;D

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.68

MutPred

0.98

Loss of glycosylation at S142 (P = 0.1399);Loss of glycosylation at S142 (P = 0.1399);.;Loss of glycosylation at S142 (P = 0.1399);

MVP

1.0

MPC

0.77

ClinPred

1.0

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

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