ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.1252G>A (p.Glu418Lys)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic(1); Likely pathogenic(7); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000527.5(LDLR):c.1252G>A (p.Glu418Lys)
Variation ID: 225182 Accession: VCV000225182.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11113343 (GRCh38) [ NCBI UCSC ] 19: 11224019 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 16, 2016 Feb 14, 2024 Dec 20, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000527.5:c.1252G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Glu418Lys missense NM_001195798.2:c.1252G>A NP_001182727.1:p.Glu418Lys missense NM_001195799.2:c.1129G>A NP_001182728.1:p.Glu377Lys missense NM_001195800.2:c.748G>A NP_001182729.1:p.Glu250Lys missense NM_001195803.2:c.871G>A NP_001182732.1:p.Glu291Lys missense NC_000019.10:g.11113343G>A NC_000019.9:g.11224019G>A NG_009060.1:g.28963G>A LRG_274:g.28963G>A LRG_274t1:c.1252G>A - Protein change
- E418K, E250K, E377K, E291K
- Other names
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- Canonical SPDI
- NC_000019.10:11113342:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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LDLR | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3998 | 4269 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Dec 19, 2019 | RCV000210833.9 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Dec 20, 2023 | RCV001181607.13 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Apr 03, 2016)
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criteria provided, single submitter
Method: literature only
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Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
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SNPedia
Accession: SCV000267119.1
First in ClinVar: Apr 16, 2016 Last updated: Apr 16, 2016 |
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Likely pathogenic
(Mar 25, 2016)
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criteria provided, single submitter
Method: literature only
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Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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LDLR-LOVD, British Heart Foundation
Accession: SCV000295328.2
First in ClinVar: Jul 29, 2016 Last updated: May 19, 2018 |
Number of individuals with the variant: 1
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Likely pathogenic
(Nov 05, 2016)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation
Additional submitter:
Centre of Molecular Biology and Gene Therapy, University Hospital Brno
Accession: SCV000540807.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Number of individuals with the variant: 1
Clinical Features:
Hypercholesterolemia (present)
Age: 20-29 years
Sex: female
Ethnicity/Population group: Caucasian
Geographic origin: Czech Republic
Tissue: Whole blood
Method: ADH Master kit (Multiplicom)
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Likely pathogenic
(Mar 01, 2016)
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criteria provided, single submitter
Method: research
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Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory of Genetics and Molecular Cardiology, University of São Paulo
Study: HipercolBrasil
Accession: SCV000588569.1 First in ClinVar: Aug 13, 2017 Last updated: Aug 13, 2017 |
Observation 1: Observation 2:
Comment on evidence:
Assay description:Comp htz (with c.1845+2T>C) patients' fibroblasts, 125I-LDL, just binding
Result:
28% LDL-LDLR binding
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Likely pathogenic
(Mar 01, 2016)
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criteria provided, single submitter
Method: research
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Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Iberoamerican FH Network
Accession: SCV000748144.1
First in ClinVar: May 19, 2018 Last updated: May 19, 2018 |
Observation 1: Observation 2:
Comment on evidence:
Assay Description:Comp htz (with c.1845+2T>C) patients' fibroblasts, 125I-LDL, just binding
Result:
28% LDL-LDLR binding
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Uncertain significance
(Jan 22, 2020)
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criteria provided, single submitter
Method: curation
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Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001422750.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 02, 2022 |
Comment:
The p.Glu418Lys variant in LDLR has been reported in 2 individuals (1 Japanese) with familial hypercholesterolemia (PMID: 27050191, 12417285), and has been identified in 0.0009% … (more)
The p.Glu418Lys variant in LDLR has been reported in 2 individuals (1 Japanese) with familial hypercholesterolemia (PMID: 27050191, 12417285), and has been identified in 0.0009% (1/113532) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs869320651). This variant has also been reported in ClinVar as likely pathogenic (Variation ID: 225182). 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, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP3, PS4_supporting (Richards 2015). (less)
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Likely pathogenic
(Dec 19, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002022660.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002186180.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 418 of the LDLR protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 418 of the LDLR protein (p.Glu418Lys). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 12417285, 18718593, 27050191, 31491741, 32331935). This variant is also known as E397K. ClinVar contains an entry for this variant (Variation ID: 225182). 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 with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LDLR function (PMID: 29874871). This variant disrupts the p.Glu418 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 19062533, 28235710), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Jun 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV001346786.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant (also known as p.Glu397Lys in the mature protein) replaces glutamic acid with lysine in the LDLR type B repeat 1 of the … (more)
This missense variant (also known as p.Glu397Lys in the mature protein) replaces glutamic acid with lysine in the LDLR type B repeat 1 of the EGF precursor homology domain of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown a ~70% reduction in LDL binding activity in cells from a severely affected pediatric individual who was compound heterozygous for this variant and a pathogenic c.1845+2T>C variant (PMID: 18718593). This LDLR variant has been reported in several heterozygous individuals affected with familial hypercholesterolemia (PMID: 18718593, 29292049, 32331935, 33533259, 34176852, 35929461), and in an individual affected with coronary artery disease (PMID: 27050191). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in an individual affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 18718593). This variant has been identified in 1/251204 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Characterization of Polyvascular Disease in Heterozygous Familial Hypercholesterolemia: Its Association With Circulating Lipoprotein(a) Levels. | Funabashi S | Journal of the American Heart Association | 2022 | PMID: 35929461 |
Universal Screening for Familial Hypercholesterolemia in Children in Kagawa, Japan. | Matsunaga K | Journal of atherosclerosis and thrombosis | 2022 | PMID: 34176852 |
Patients With LDLR and PCSK9 Gene Variants Experienced Higher Incidence of Cardiovascular Outcomes in Heterozygous Familial Hypercholesterolemia. | Doi T | Journal of the American Heart Association | 2021 | PMID: 33533259 |
A catalog of the pathogenic mutations of LDL receptor gene in Japanese familial hypercholesterolemia. | Tada H | Journal of clinical lipidology | 2020 | PMID: 32331935 |
Impact of LDLR and PCSK9 pathogenic variants in Japanese heterozygous familial hypercholesterolemia patients. | Hori M | Atherosclerosis | 2019 | PMID: 31491741 |
Validation of LDLr Activity as a Tool to Improve Genetic Diagnosis of Familial Hypercholesterolemia: A Retrospective on Functional Characterization of LDLr Variants. | Benito-Vicente A | International journal of molecular sciences | 2018 | PMID: 29874871 |
Assessment of arterial stiffness in patients with familial hypercholesterolemia. | Tada H | Journal of clinical lipidology | 2018 | PMID: 29292049 |
The genetic spectrum of familial hypercholesterolemia in the central south region of China. | Xiang R | Atherosclerosis | 2017 | PMID: 28235710 |
Diagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia. | Khera AV | Journal of the American College of Cardiology | 2016 | PMID: 27050191 |
Update of Japanese common LDLR gene mutations and their phenotypes: Mild type mutation L547V might predominate in the Japanese population. | Miyake Y | Atherosclerosis | 2009 | PMID: 18718593 |
[The spectrum of mutations in the low-density lipoprotein receptor gene in the Russian population]. | Voevoda MI | Genetika | 2008 | PMID: 19062533 |
Molecular genetic analysis of familial hypercholesterolemia: spectrum and regional difference of LDL receptor gene mutations in Japanese population. | Yu W | Atherosclerosis | 2002 | PMID: 12417285 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/7c2381f2-f4e1-44e1-9481-3054b1e2c394 | - | - | - | - |
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Text-mined citations for this variant ...
HelpRecord last updated Mar 30, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.