Submissions for variant NM_000527.5(LDLR):c.418G>A (p.Glu140Lys)

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000238418	SCV002506364	pathogenic	Hypercholesterolemia, familial, 1	2021-12-13	reviewed by expert panel	curation	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.
LDLR-LOVD, British Heart Foundation	RCV000238418	SCV000294698	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000238418	SCV000322897	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research	0/100 healthy control individuals; 0/60 healthy control individuals; 0/190 non-FH alleles
Robarts Research Institute, Western University	RCV000238418	SCV000484695	likely pathogenic	Hypercholesterolemia, familial, 1		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	RCV000238418	SCV000503154	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 5 , family members = 2 with co-segregation / FH Philippine / Software predictions: Damaging
Invitae	RCV000775038	SCV000544698	pathogenic	Familial hypercholesterolemia	2023-08-07	criteria provided, single submitter	clinical testing	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).
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000238418	SCV000583674	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000238418	SCV000588499	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Fundacion Hipercolesterolemia Familiar	RCV000238418	SCV000607454	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Iberoamerican FH Network	RCV000238418	SCV000748038	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV000775038	SCV000909135	pathogenic	Familial hypercholesterolemia	2023-09-05	criteria provided, single submitter	clinical testing	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.
CeGaT Center for Human Genetics Tuebingen	RCV001090450	SCV001246003	pathogenic	not provided	2019-06-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002327170	SCV002626623	pathogenic	Cardiovascular phenotype	2017-11-27	criteria provided, single submitter	clinical testing	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; Garc&iacute;a-Garc&iacute;a 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; Kuhrov&aacute; 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.
New York Genome Center	RCV000238418	SCV002764529	pathogenic	Hypercholesterolemia, familial, 1	2020-12-16	criteria provided, single submitter	clinical testing	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.
Revvity Omics, Revvity	RCV000238418	SCV003819509	pathogenic	Hypercholesterolemia, familial, 1	2022-10-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital Muenster	RCV003231417	SCV003929521	pathogenic	See cases	2023-04-05	criteria provided, single submitter	clinical testing	ACMG categories: PS1,PM1,PM2,PP2,PP5
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238418	SCV000606111	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research