ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.693C>A (p.Cys231Ter)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000527.5(LDLR):c.693C>A (p.Cys231Ter)
Variation ID: 3730 Accession: VCV000003730.32
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11105599 (GRCh38) [ NCBI UCSC ] 19: 11216275 (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 4, 2013 Sep 16, 2024 Jul 30, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000527.5:c.693C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Cys231Ter nonsense NM_001195798.2:c.693C>A NP_001182727.1:p.Cys231Ter nonsense NM_001195799.2:c.570C>A NP_001182728.1:p.Cys190Ter nonsense NM_001195800.2:c.314-1793C>A intron variant NM_001195803.2:c.314-966C>A intron variant NC_000019.10:g.11105599C>A NC_000019.9:g.11216275C>A NG_009060.1:g.21219C>A LRG_274:g.21219C>A LRG_274t1:c.693C>A LRG_274p1:p.Cys231Ter - Protein change
- C231*, C190*
- Other names
- C210*
- FH London 3
- NP_000518.1:p.C231*
- Canonical SPDI
- NC_000019.10:11105598:C: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 |
4073 | 4349 |
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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Pathogenic/Likely pathogenic (9) |
criteria provided, multiple submitters, no conflicts
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Mar 30, 2017 | RCV000003928.24 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jul 30, 2024 | RCV000775046.17 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 8, 2022 | RCV002362558.9 |
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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Pathogenic
(Dec 16, 2016)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
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Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix
Accession: SCV000503223.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Comment:
subjects mutated among 2600 FH index cases screened = 4 , family members = 9 with co-segregation
Number of individuals with the variant: 4
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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: SCV000540756.1
First in ClinVar: Apr 08, 2017 Last updated: Apr 08, 2017 |
Number of individuals with the variant: 1
Clinical Features:
Hypercholesterolemia (present) , Ischemic stroke (present)
Age: 50-59 years
Sex: male
Ethnicity/Population group: Caucasian
Geographic origin: Czech Republic
Tissue: Whole blood
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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: SCV000588513.1 First in ClinVar: Aug 13, 2017 Last updated: Aug 13, 2017 |
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Pathogenic
(Jun 18, 2018)
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criteria provided, single submitter
Method: clinical testing
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Familial hypercholesterolemias
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000909144.1
First in ClinVar: May 20, 2019 Last updated: May 20, 2019 |
Comment:
Pathogenic variant based on current evidence: This variant is a single nucleotide substitution in exon 4 of the LDLR gene, which creates a premature translation … (more)
Pathogenic variant based on current evidence: This variant is a single nucleotide substitution in exon 4 of the LDLR gene, which creates a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional assays have not been performed for this variant. While this variant is rare in the general population (0/277264 chromosomes in the Genome Aggregation Database (gnomAD)), it has been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 8093663, 16389549, 22883975). Truncating variants in LDLR are known to be pathogenic (PMID: 20809525). Based on available evidence, this variant is classified as Pathogenic. (less)
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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: SCV000294914.2
First in ClinVar: Jul 29, 2016 Last updated: May 03, 2018 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 1
Observation 3:
Number of individuals with the variant: 1
Observation 4:
Number of individuals with the variant: 1
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Likely pathogenic
(-)
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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:
germline
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Robarts Research Institute, Western University
Accession: SCV000484681.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Number of individuals with the variant: 3
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Pathogenic
(Mar 30, 2017)
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criteria provided, single submitter
Method: clinical testing
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Familial Hypercholesterolemia
Affected status: yes
Allele origin:
germline
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U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille
Accession: SCV000583728.1
First in ClinVar: Apr 08, 2017 Last updated: Apr 08, 2017
Comment:
ACMG Guidelines: Pathogenic (i)
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Number of individuals with the variant: 2
Clinical Features:
Hyperbetalipoproteinemia (present) , Hypercholesterolemia (present)
Indication for testing: Familial Hypercholesterolemia
Sex: mixed
Geographic origin: France
Comment on evidence:
Dutch Lipid Clinic Scoring : Definite FH
Secondary finding: no
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Pathogenic
(Nov 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000952013.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Cys231*) in the LDLR gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Cys231*) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with familial hypercholesterolemia (PMID: 8093663, 10559517, 16389549, 20145306, 21310417, 22698793, 22883975, 27680772). This variant is also known as Cys210X. ClinVar contains an entry for this variant (Variation ID: 3730). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002664339.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.C231* pathogenic mutation (also known as c.693C>A), located in coding exon 4 of the LDLR gene, results from a C to A substitution at … (more)
The p.C231* pathogenic mutation (also known as c.693C>A), located in coding exon 4 of the LDLR gene, results from a C to A substitution at nucleotide position 693. This changes the amino acid from a cysteine to a stop codon within coding exon 4. This alteration (also described as p.C210*) has been reported in familial hypercholesterolemia cohorts (Gudnason V et al. Arterioscler. Thromb., 1993 Jan;13:56-63; Chmara M et al. J. Appl. Genet., 2010;51:95-106; Dušková L et al. Atherosclerosis, 2011 May;216:139-45). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Jul 30, 2024)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005202233.1
First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
Comment:
Variant summary: LDLR c.693C>A (p.Cys231X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: LDLR c.693C>A (p.Cys231X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 244710 control chromosomes. c.693C>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Martin_2016). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 27680772). ClinVar contains an entry for this variant (Variation ID: 3730). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jul 09, 2008)
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no assertion criteria provided
Method: clinical testing
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Familial hypercholesterolemia
Affected status: yes
Allele origin:
germline
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Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital
Accession: SCV000268583.1
First in ClinVar: May 21, 2016 Last updated: May 21, 2016 |
Number of individuals with the variant: 1
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Pathogenic
(Jul 21, 2023)
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no assertion criteria provided
Method: research
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Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
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deCODE genetics, Amgen
Accession: SCV004022251.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
The variant NM_000527.5:c.693C>A (chr19:11105599) in LDLR was detected in 3 heterozygotes out of 58K WGS Icelanders (MAF= 0,003%). Following imputation in a set of 166K … (more)
The variant NM_000527.5:c.693C>A (chr19:11105599) in LDLR was detected in 3 heterozygotes out of 58K WGS Icelanders (MAF= 0,003%). Following imputation in a set of 166K Icelanders (4 imputed heterozygotes) we observed an association with LDL cholesterol using measurements from 128289 individuals (Effect (SD)= 3.59, P= 4.14e-10) and Non-HDL cholesterol using measurements from 136901 individuals (Effect (SD)= 3.26, P= 1.50e-08). This variant has been reported in ClinVar previously as pathogenic/likely pathogenic. Based on ACMG criteria (PVS1, PS4, PM2 ) this variant classifies as pathogenic. (less)
Number of individuals with the variant: 4
Ethnicity/Population group: Icelandic
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Pathogenic
(Jan 01, 1993)
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no assertion criteria provided
Method: literature only
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FH LONDON 3
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000024093.2
First in ClinVar: Apr 04, 2013 Last updated: Jun 23, 2019 |
Comment on evidence:
In an Irish subject with familial hypercholesterolemia (FHCL1; 143890), 1 of 200 patients attending lipid clinics in the London area, Gudnason et al. (1993) found … (more)
In an Irish subject with familial hypercholesterolemia (FHCL1; 143890), 1 of 200 patients attending lipid clinics in the London area, Gudnason et al. (1993) found a GCG-to-GAG transversion changing cys210 to a stop codon. (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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Analysis of LDLR variants from homozygous FH patients carrying multiple mutations in the LDLR gene. | Jiang L | Atherosclerosis | 2017 | PMID: 28645073 |
Genetic diagnosis of familial hypercholesterolaemia using a rapid biochip array assay for 40 common LDLR, APOB and PCSK9 mutations. | Martin R | Atherosclerosis | 2016 | PMID: 27680772 |
Genetic analysis of familial hypercholesterolaemia in Western Australia. | Hooper AJ | Atherosclerosis | 2012 | PMID: 22883975 |
The molecular basis of familial hypercholesterolemia in the Czech Republic: spectrum of LDLR mutations and genotype-phenotype correlations. | Tichý L | Atherosclerosis | 2012 | PMID: 22698793 |
An APEX-based genotyping microarray for the screening of 168 mutations associated with familial hypercholesterolemia. | Dušková L | Atherosclerosis | 2011 | PMID: 21310417 |
Molecular spectrum of autosomal dominant hypercholesterolemia in France. | Marduel M | Human mutation | 2010 | PMID: 20809525 |
Molecular characterization of Polish patients with familial hypercholesterolemia: novel and recurrent LDLR mutations. | Chmara M | Journal of applied genetics | 2010 | PMID: 20145306 |
Mutational analysis in UK patients with a clinical diagnosis of familial hypercholesterolaemia: relationship with plasma lipid traits, heart disease risk and utility in relative tracing. | Humphries SE | Journal of molecular medicine (Berlin, Germany) | 2006 | PMID: 16389549 |
Mutation screening and genotype:phenotype correlation in familial hypercholesterolaemia. | Graham CA | Atherosclerosis | 1999 | PMID: 10559517 |
Identification of recurrent and novel mutations in exon 4 of the LDL receptor gene in patients with familial hypercholesterolemia in the United Kingdom. | Gudnason V | Arteriosclerosis and thrombosis : a journal of vascular biology | 1993 | PMID: 8093663 |
Text-mined citations for this variant ...
HelpRecord last updated Sep 29, 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.