chr19-11105324-G-A

Position:

chr19-11105324-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP1_StrongPM1PM2PP3PP4PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.418G>A (p.Glu140Lys) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PP1_Strong, PM1, PM2, PP3, PP4 and PS4_Supporting) 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: PP1_strong - variant segregates with FH phenotype in 8 informative meioses from 4 families from Instituto Nacional de Saude Doutor Ricardo Jorge and Laboratory of Genetics and Molecular Cardiology, so PP1_Strong is met.PM1 - variant is missense in exon 4 and meets PM2 criteria, so PM1 is met.PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met.PP3 - REVEL = 0.965, it is above 0.75, so PP3 is met.PP4 - Variant meets PM2 and was identified in 2 unrelated index cases who fulfill SB criteria from Instituto Nacional de Saude Doutor Ricardo Jorge, so PP4 is met.PS4_supporting - variant meets PM2. Identified in 2 unrelated index cases who fulfill SB criteria from Instituto Nacional de Saude Doutor Ricardo Jorge, PS4_supporting is met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10584911/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:18

Conservation

PhyloP100: 9.88

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 11 ACMG points.

PS4

PM1

PM2

PP1

PP3

PP4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.418G>A	p.Glu140Lys	missense_variant	4/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.418G>A	p.Glu140Lys	missense_variant	4/18	1	NM_000527.5	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152192

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461506

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727096

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:13

Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	Dec 16, 2016	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Dec 13, 2021	The NM_000527.5(LDLR):c.418G>A (p.Glu140Lys) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PP1_Strong, PM1, PM2, PP3, PP4 and PS4_Supporting) 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: PP1_strong - variant segregates with FH phenotype in 8 informative meioses from 4 families from Instituto Nacional de Saude Doutor Ricardo Jorge and Laboratory of Genetics and Molecular Cardiology, so PP1_Strong is met. PM1 - variant is missense in exon 4 and meets PM2 criteria, so PM1 is met. PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met. PP3 - REVEL = 0.965, it is above 0.75, so PP3 is met. PP4 - Variant meets PM2 and was identified in 2 unrelated index cases who fulfill SB criteria from Instituto Nacional de Saude Doutor Ricardo Jorge, so PP4 is met. PS4_supporting - variant meets PM2. Identified in 2 unrelated index cases who fulfill SB criteria from Instituto Nacional de Saude Doutor Ricardo Jorge, PS4_supporting is met. -
Likely pathogenic, criteria provided, single submitter	research	Iberoamerican FH Network	Mar 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Dec 16, 2020	The heterozygous c.418G>A (p.Glu140Lys) missense variant identified in the LDLR gene has been reported in multiple individuals affected with familial hypercholesterolemia [PMID:1301956, 8347689, 31491741, and more]. The variant is also known as p.Glu119Lys in the literature, and is reported in ClinVar as Pathogenic/Likely Pathogenic by multiple independent laboratories [VarID:251213]. The p.Glu140Lys variant has 0.00001314 allele frequency in the gnomAD database [2 out of 152,192 heterozygous alleles, no homozygotes] suggesting it is not a common benign variant in the populations represented in that database. The variant affects an evolutionarily conserved reside and is predicted deleterious by multiple in silico prediction tools. Functional studies demonstrate that the p.Glu140Lysvariant results in significantly reduced LDLR activity, and protein instability with reduced internalization and degradation [PMID:1301956, 8347689]. Based on the available evidence, the heterozygous p.Glu140Lys variant identified in the LDLR gene is reported as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 23, 2023	This missense variant replaces glutamic acid with lysine at codon 140 of the LDLR protein. This variant is also known as p.Glu119Lys in the mature protein and as FH-Philippines and FH Durban-2 in the literature. This variant alters a conserved glutamic acid residue in the third LDLR type A repeat of the ligand binding domain of the LDLR protein (a.a. 107-145), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction tool suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). Functional studies with compound heterozygous patient fibroblasts showed <10-30% LDLR activity compared to wild type and LDLR protein instability (PMID: 1301956, 8347689, 18718593). This variant has been reported in 10+ individuals diagnosed with familial hypercholesterolemia (PMID: 1301956, 8347689, 10532689, 11668627, 11668640, 15359125, 18718593, 19446849, 21722902, 23375686, 25962062, 34998859) and shown to segregate with disease in four families (PMID: 15359125, 34998859). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Glu140Asp, is considered to be disease-causing (ClinVar variation ID: 251216), suggesting that glutamic acid at this position is important for LDLR protein function. Based on available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 01, 2022	- -
Likely pathogenic, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	0/100 healthy control individuals; 0/60 healthy control individuals; 0/190 non-FH alleles -

Familial hypercholesterolemia

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 05, 2023	This missense variant replaces glutamic acid with lysine at codon 140 of the LDLR protein. This variant is also known as p.Glu119Lys in the mature protein and as FH-Philippines and FH Durban-2 in the literature. This variant alters a conserved glutamic acid residue in the third LDLR type A repeat of the ligand binding domain of the LDLR protein (a.a. 107-145), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction tool suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies with compound heterozygous patient fibroblasts showed <10-30% LDLR activity compared to wild type and LDLR protein instability (PMID: 1301956, 8347689, 18718593). This variant has been reported in 10+ individuals diagnosed with familial hypercholesterolemia (PMID: 1301956, 8347689, 10532689, 11668627, 11668640, 15359125, 18718593, 19446849, 21722902, 23375686, 25962062, 34998859) and shown to segregate with disease in four families (PMID: 15359125, 34998859). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Glu140Asp, is considered to be disease-causing (ClinVar variation ID: 251216), suggesting that glutamic acid at this position is important for LDLR protein function. Based on available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 07, 2023	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. For these reasons, this variant has been classified as Pathogenic. 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: 11754108; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 251213). This variant is also known as p.Glu119Lys. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 1301956, 8347689, 10532689, 11668627, 11668640, 15359125, 17539906, 18718593, 19446849, 21310417, 21722902, 23375686, 25962062, 26343872). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 140 of the LDLR protein (p.Glu140Lys). -

See cases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Apr 05, 2023

ACMG categories: PS1,PM1,PM2,PP2,PP5 -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2019

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 27, 2017

The p.E140K pathogenic mutation (also known as c.418G>A), located in coding exon 4 of the LDLR gene, results from a G to A substitution at nucleotide position 418. The glutamic acid at codon 140 is replaced by lysine, an amino acid with similar properties. This alteration, also referred to as E119K, has been reported in a number of individuals with familial hypercholesterolemia (FH) around the world (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Rubinsztein DC et al. Biochim. Biophys. Acta, 1993 Aug;1182:75-82; Maruyama T et al. Arterioscler. Thromb. Vasc. Biol., 1995 Oct;15:1713-8; Jensen HK et al. Atherosclerosis, 1999 Oct;146:337-44; García-García AB et al. Hum. Mutat., 2001 Nov;18:458-9; Vaca G et al. Atherosclerosis, 2011 Oct;218:391-6; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Shin DG et al. Atherosclerosis, 2015 Nov;243:53-8). Alterations affecting the same amino acid residue, E140D, E140G and E140A, have also been reported in association with FH (Fouchier SW et al. Hum. Genet., 2001 Dec;109:602-15; Kuhrová V et al. Hum. Mutat., 2002 Jan;19:80; Durst R et al. Atherosclerosis, 2017 Feb;257:55-63). 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

0.93

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

D;.;.;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Pathogenic

0.84

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.2

H;.;.;H

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-3.6

D;D;D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.89

MutPred

0.93

Gain of ubiquitination at E140 (P = 0.0051);Gain of ubiquitination at E140 (P = 0.0051);.;Gain of ubiquitination at E140 (P = 0.0051);

MVP

1.0

MPC

0.86

ClinPred

1.0

GERP RS

5.6

Varity_R

0.99

gMVP

1.0

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