rs879254781
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM3PP3PP4PS4_Moderate
This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1069G>A (p.Glu357Lys) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PM3, PS4_moderate, PP3 and PP4) 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:PM2 - This variant is absent from gnomAD (gnomAD v2.1.1).PM3 - Variant meets PM2 and is identified in 2 compound heterozygous cases (1 case in PMID:30179711 (Lock et al., 2018) with LDL = 23.89 mmol/L and also LDLR c.2043C>A - Pathogenic by these guidelines; 1 case in PMID:19026292 (Kolansky et al., 2008) with LDL = 16.29 mmol/L and also LDLR c.1775G>A - Pathogenic by these guidelines).PS4_moderate - Variant meets PM2 and is identified in 8 unrelated index cases (3 cases with DLCN criteria>=6 and 1 case with Simon-Broome criteria of possible FH from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 1 unrelated case fulfilling internationally accepted criteria (Defesche 2000; Goldstein et al. 1995) for definite heterozygous FH published in PMID:11810272 (Fouchier et al., 2001), The Netherlands; 1 unrelated case fulfilling WHO criteria published in PMID:21382890 (van der Graaf et al., 2011), The Netherlands; 1 unrelated case fulfilling WHO criteria published in PMID:10735632 (Lombardi et al., 2000), The Netherlands; 1 unrelated case with DLCN criteria>=6 published in PMID:28502510 (Bañares et al., 2017), Argentina).PP3 - REVEL = 0.976.PP4 - Variant meets PM2 and is identified in at least one index case who fufills clinical criteria for FH (see PS4 for details), after alternative causes for high cholesterol were excluded. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585290/MONDO:0007750/013
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
LDLR
NM_000527.5 missense
NM_000527.5 missense
Scores
16
2
1
Clinical Significance
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PS4
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PM3
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.
PP4
For more information check the summary or visit ClinGen Evidence Repository.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LDLR | NM_000527.5 | c.1069G>A | p.Glu357Lys | missense_variant | 8/18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| LDLR | ENST00000558518.6 | c.1069G>A | p.Glu357Lys | missense_variant | 8/18 | 1 | NM_000527.5 | ENSP00000454071 | P3 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152178Hom.: 0 Cov.: 31
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461212Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726958
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GnomAD4 genome 0.00000657 AC: 1AN: 152178Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74340
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:15Uncertain:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:6Uncertain:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Nov 16, 2023 | Criteria applied: PS4_MOD,PM3,PM2_SUP,PP3,PP4 - |
| Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille | Mar 30, 2017 | - - |
| Likely pathogenic, reviewed by expert panel | curation | ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Apr 28, 2023 | The NM_000527.5(LDLR):c.1069G>A (p.Glu357Lys) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PM3, PS4_moderate, PP3 and PP4) 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: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1). PM3 - Variant meets PM2 and is identified in 2 compound heterozygous cases (1 case in PMID: 30179711 (Lock et al., 2018) with LDL = 23.89 mmol/L and also LDLR c.2043C>A - Pathogenic by these guidelines; 1 case in PMID: 19026292 (Kolansky et al., 2008) with LDL = 16.29 mmol/L and also LDLR c.1775G>A - Pathogenic by these guidelines). PS4_moderate - Variant meets PM2 and is identified in 8 unrelated index cases (3 cases with DLCN criteria>=6 and 1 case with Simon-Broome criteria of possible FH from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 1 unrelated case fulfilling internationally accepted criteria (Defesche 2000; Goldstein et al. 1995) for definite heterozygous FH published in PMID: 11810272 (Fouchier et al., 2001), The Netherlands; 1 unrelated case fulfilling WHO criteria published in PMID: 21382890 (van der Graaf et al., 2011), The Netherlands; 1 unrelated case fulfilling WHO criteria published in PMID: 10735632 (Lombardi et al., 2000), The Netherlands; 1 unrelated case with DLCN criteria>=6 published in PMID: 28502510 (Bañares et al., 2017), Argentina). PP3 - REVEL = 0.976. PP4 - Variant meets PM2 and is identified in at least one index case who fufills clinical criteria for FH (see PS4 for details), after alternative causes for high cholesterol were excluded. - |
| 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 | subjects mutated among 2600 FH index cases screened = 12 , family members = 11 with co-segregation / FH-Paris-7 / Software predictions: Damaging - |
| Uncertain significance, criteria provided, single submitter | research | Iberoamerican FH Network | Mar 01, 2016 | - - |
| Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
not provided Pathogenic:4
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Jul 13, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 28, 2024 | Observed with a pathogenic variant on the opposite allele (in trans) in two patients with a clinical diagnosis of HoFH (PMID: 19026292, 30179711); 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 FH Paris-7 and p.(E336K); This variant is associated with the following publications: (PMID: 22390909, 1301956, 28502510, 30179711, 32719484, 33740630, 34037665, 33087929, 33955087, 35177841, 19026292, 11810272, 21382890, 10735632) - |
Familial hypercholesterolemia Pathogenic:3
| Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 22, 2019 | This missense variant (also known as p.Glu336Lys in the mature protein and as FH Paris-7) replaces glutamic acid with lysine at codon 357 in the EGF-like repeat B of the EGF precursor homology domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. Experimental functional study has shown that this variant may cause defect in protein transport or recycling (PMID: 1301956). This variant has been reported in over ten individuals affected with familial hypercholesterolemia (PMID: 10735632, 11810272, 1301956, 20506408, 21382890, 23833242). This variant has been reported in compound heterozygosity with c.2034C>A (p.Cys681*) in a young child affected with familial hypercholesterolemia and prominent corneal arcus (PMID: 30179711). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 22, 2020 | The p.Glu357Lys variant in LDLR has been reported in at least 11 individuals with familial hypercholesterolemia, segregated with disease in 6 affected relatives from 1 family (PMID: 15199436), and was absent from large population studies. This variant has also been reported in ClinVar as having conflicting interpretations of pathogenicity (Variation ID: 251649). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PP1_moderate, PP3, PS4_supporting (Richards 2015). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 16, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Glu357 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 16250003), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 251649). This variant is also known as E336K. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 1301956, 10735632, 15199436, 28502510, 30179711; Invitae). 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 357 of the LDLR protein (p.Glu357Lys). - |
Homozygous familial hypercholesterolemia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 07, 2019 | The p.Glu357Lys variant in LDLR, also known as p.Glu336Lys or FH Paris 7, has been reported in the heterozygous state at least 10 probands with hypercholestrolemia (Hobbs 1992, Lombardi 2000, Huijgen 2010, Fouchier 2014, Banares 2017) and segregated with disease in at least 4 affected family members (Kusters 2013). In addition, this variant was identified in the compound heterozygous state with another pathogenic variant in a child with a severe presentation. It was inherited from his mother who had borderline high cholesterol (Lock 2018). This variant has been identified in multiple individuals in a large cohort from the Netherlands with mutation carriers (n=27) having mean LDL of 6.51 mmol/L compared to family members who were not carriers of the variant (n=100) with mean LDL of 3.37 mmol/L (Fouchier 2014). This variant is absent from large population studies but has been reported in ClinVar (Variation ID # 251649). Computational prediction tools and conservation analysis are consistent with pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant familial hypercholesterolemia. ACMG/AMP Criteria applied: PS4, PM2, PM3, PP1, PP3. - |
Cardiovascular phenotype Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 24, 2022 | The p.E357K variant (also known as c.1069G>A), located in coding exon 8 of the LDLR gene, results from a G to A substitution at nucleotide position 1069. The glutamic acid at codon 357 is replaced by lysine, an amino acid with similar properties. This variant was detected in a pediatric clinical homozygous familial hypercholesterolemia (FH) case with a second LDLR mutation in trans, as well as in his heterozygous affected father (Lock JH et al. J AAPOS, 2018 Dec;22:467-468). This variant (also described as legacy p.E336K and FH Paris-7) has been reported in numerous FH cohorts, although clinical details were limited in most cases (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Lombardi MP et al. Clin. Genet., 2000 Feb;57:116-24; Leren TP et al. Semin Vasc Med, 2004 Feb;4:75-85; Kolansky DM et al. Am. J. Cardiol., 2008 Dec;102:1438-43; Huijgen R et al. Hum. Mutat., 2010 Jun;31:752-60). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;.;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.;.;.;.;H
MutationTaster
Benign
D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D;D
Polyphen
D;.;.;.;.;.
Vest4
MutPred
Gain of methylation at E357 (P = 0.0038);Gain of methylation at E357 (P = 0.0038);.;.;.;Gain of methylation at E357 (P = 0.0038);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at