rs730882103
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_000527.5(LDLR):c.1510A>G(p.Lys504Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000025 ( 0 hom. )
Consequence
LDLR
NM_000527.5 missense
NM_000527.5 missense
Scores
2
5
12
Clinical Significance
Conservation
PhyloP100: 2.02
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 Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.837
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.1510A>G | p.Lys504Glu | missense_variant | 10/18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.1510A>G | p.Lys504Glu | missense_variant | 10/18 | 1 | NM_000527.5 | ENSP00000454071 | P3 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152142Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251454Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135910
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GnomAD4 exome AF: 0.0000253 AC: 37AN: 1461864Hom.: 0 Cov.: 35 AF XY: 0.0000289 AC XY: 21AN XY: 727230
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152142Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74326
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:9Benign:2Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hypercholesterolemia, familial, 1 Uncertain:4Benign:2
Likely benign, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Uncertain significance, 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 | subject mutated among 2600 FH index cases screened = 1/Software predictions: Benign - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 15, 2023 | This missense variant (also known as p.Lys483Glu in the mature protein) replaces lysine with glutamic acid at codon 504 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A cell-based experimental study has shown that this variant does not disrupt LDL uptake function of the protein (PMID: 25647241). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 15199436, 25647241; Color internal data). This variant has also been observed in compound heterozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 27784735). Additionally, this variant has been reported in individuals affected with myocardial infarction (PMID: 25487149). This variant has been identified in 3/251454 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille | Jan 31, 2024 | This missense variant LDLR: c.1510A>G (p.Lys504Glu), replaces lysine with glutamic acid at codon 504 of the LDLR protein. According to updated genomic data and to ClinGen FH VCEP criteria issued in 2022 (PMID: 34906454) for the validation of pathogenicity of LDLR variants, this variant may now be classified as “Variant of Uncertain Significance” from conflicting evidence as follows. This variant is located within a conserved (REVEL=0.529) functional domain (LDLR Class B3) involved in LDL receptor recycling to the plasma membrane (PP3-supporting). This variant is observed with a frequency <0.02% (PM2), in the general population (GnomAD= 0.0000197, no homozygotes). It was observed in hypercholesterolemic individuals and reported to cosegregate with FH in independent families of European ancestry (PS4-supporting). However, level 1 in-vitro functional studies have shown that this variant has a neutral effect on LDLR function (BS3). - |
Benign, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
Uncertain significance, criteria provided, single submitter | research | Fundacion Hipercolesterolemia Familiar | Mar 01, 2016 | - - |
Familial hypercholesterolemia Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 30, 2021 | This sequence change replaces lysine with glutamic acid at codon 504 of the LDLR protein (p.Lys504Glu). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is present in population databases (rs730882103, ExAC 0.008%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 15199436, 19318025, 25487149). ClinVar contains an entry for this variant (Variation ID: 183117). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect LDLR function (PMID: 25647241). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 22, 2020 | The p.Lys504Glu variant in LDLR has been reported in 1 Italian and 2 Norwegian individuals with familial hypercholesterolemia (PMID: 25647241, PMID: 15199436), but has been identified in 0.003% (3/113736) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs730882103). This variant has also been reported in ClinVar as having conflicint interpretations of pathogenicity (Variation ID: rs730882103). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_supporting (Richards 2015). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 03, 2023 | This missense variant (also known as p.Lys483Glu in the mature protein) replaces lysine with glutamic acid at codon 504 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A cell-based experimental study has shown that this variant does not disrupt LDL uptake function of the protein (PMID: 25647241). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 15199436, 25647241; Color internal data). This variant has also been observed in compound heterozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 27784735). Additionally, this variant has been reported in individuals affected with myocardial infarction (PMID: 25487149). This variant has been identified in 3/251454 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 13, 2024 | Variant summary: LDLR c.1510A>G (p.Lys504Glu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251454 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1510A>G has been reported in the literature in individuals affected with Familial Hypercholesterolemia without strong evidence of causality (e.g. Alonso_2009, Sanchez-Hernandez_2016, Di Taranto_2021, Futema_2021). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. At least one publication reports experimental evidence evaluating an impact on protein function (Thormaehlen_2015). These results showed no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 19318025, 25647241, 27784735, 34297352, 33508743). ClinVar contains an entry for this variant (Variation ID: 183117). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 13, 2024 | The p.K504E variant (also known as c.1510A>G), located in coding exon 10 of the LDLR gene, results from an A to G substitution at nucleotide position 1510. The lysine at codon 504 is replaced by glutamic acid, an amino acid with similar properties. This alteration has been reported in familial hypercholesterolemia (FH) cohorts (Leren TP et al. Semin Vasc Med, 2004 Feb;4:75-85; Alonso R et al. Clin Biochem, 2009 Jun;42:899-903; Sánchez-Hernández RM et al. Circ Cardiovasc Genet, 2016 Dec;9:504-510). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. - |
not provided Other:1
not provided, no classification provided | in vitro | Dept. of Genetics and Pharmacogenomics, Merck Research Labs | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Benign
DEOGEN2
Uncertain
T;.;.;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T;T;T;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
N;.;.;.;.;N
MutationTaster
Benign
D;D;N;N;N;N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N;N;N;N
REVEL
Uncertain
Sift
Benign
T;T;T;T;T;T
Sift4G
Benign
T;T;T;T;T;T
Polyphen
B;.;.;.;.;.
Vest4
MutPred
Loss of MoRF binding (P = 0.0075);Loss of MoRF binding (P = 0.0075);.;.;.;Loss of MoRF binding (P = 0.0075);
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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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