rs748944640
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PP1_StrongPM2PP3PP4PS4_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
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
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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: 2AN: 152192Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461506Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3AN XY: 727096
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152192Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74360
ClinVar
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at