rs748944640

Positions:

• chr19-11105324-G-A
• chr19-11105324-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PP1_Strong PM2 PP3 PP4 PS4_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
• Clinical Significance: Pathogenic reviewed by expert panel P:18
• Conservation: PhyloP100: 9.88

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	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	c.418G>A	p.Glu140Lys	missense_variant	4/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152192 Hom.: 0 Cov.: 33

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: 5 AN: 1461506 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727096

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: 2 AN: 152192 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74360

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

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	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H;.;.;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.6	D;D;D;D
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	D
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

Other links and lift over

dbSNP: rs748944640; hg19: chr19-11216000; COSMIC: COSV52942632; COSMIC: COSV52942632;