ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.670G>A (p.Asp224Asn)
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.670G>A (p.Asp224Asn)
Variation ID: 3706 Accession: VCV000003706.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11105576 (GRCh38) [ NCBI UCSC ] 19: 11216252 (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 Oct 15, 2016 May 1, 2024 Oct 2, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000527.5:c.670G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Asp224Asn missense NM_001195798.2:c.670G>A NP_001182727.1:p.Asp224Asn missense NM_001195799.2:c.547G>A NP_001182728.1:p.Asp183Asn missense NM_001195800.2:c.314-1816G>A intron variant NM_001195803.2:c.314-989G>A intron variant NC_000019.10:g.11105576G>A NC_000019.9:g.11216252G>A NG_009060.1:g.21196G>A LRG_274:g.21196G>A LRG_274t1:c.670G>A LRG_274p1:p.Asp224Asn P01130:p.Asp224Asn - Protein change
- D224N, D183N
- Other names
- D203N
- FH Portugal
- NP_000518.1:p.D224N
- Canonical SPDI
- NC_000019.10:11105575: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 |
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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Oct 2, 2023 | RCV000003896.15 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 6, 2022 | RCV001851629.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 25, 2022 | RCV002362557.2 |
Submissions - Germline
Classification
Help
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
(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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Fundacion Hipercolesterolemia Familiar
Study: SAFEHEART
Accession: SCV000607486.1 First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
Observation 1: Observation 2:
Comment on evidence:
Hmz patient fibroblast, 125I-LDL assays
Result:
<2% LDLR activity
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Pathogenic
(Oct 06, 2022)
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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: SCV002173713.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp224 amino acid residue in LDLR. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp224 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301956, 17539906, 23375686). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 3706). This variant is also known as D203N. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 15576851, 19843101, 30876530; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 224 of the LDLR protein (p.Asp224Asn). (less)
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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: SCV000294882.2
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
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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: yes
Allele origin:
germline
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Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge
Accession: SCV000322910.1
First in ClinVar: Oct 15, 2016 Last updated: Oct 15, 2016 |
Comment:
0/190 non-FH alleles; 0/100 healthy control individuals
Observation 1: Observation 2:
Comment on evidence:
Homozygous patient fibroblast, 125I-LDL assays
Result:
<2% LDLR activity
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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: SCV000484692.1
First in ClinVar: Dec 17, 2016 Last updated: Dec 17, 2016 |
Number of individuals with the variant: 1
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Likely 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: SCV000503207.1
First in ClinVar: Dec 17, 2016 Last updated: Dec 17, 2016 |
Comment:
subject mutated among 2600 FH index cases screened = 1 / FH-Portugal
Number of individuals with the variant: 1
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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: SCV000583719.1
First in ClinVar: Dec 17, 2016 Last updated: Dec 17, 2016
Comment:
ACMG Guidelines: Pathogenic (ii)
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Number of individuals with the variant: 1
Clinical Features:
Hyperbetalipoproteinemia (present) , Hypercholesterolemia (present)
Indication for testing: Familial Hypercholesterolemia
Geographic origin: France
Comment on evidence:
Dutch Lipid Clinic Scoring : Definite FH
Secondary finding: no
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Pathogenic
(Oct 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
(Semidominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004829274.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This variant has been reported in multiple individuals with hypercholesterolemia (PMID: 15576851, 19843101, 30876530, 17765246, 16627557, 33231818, 33508743, 20828696, 26020417, 20828696, 33027386). It is absent … (more)
This variant has been reported in multiple individuals with hypercholesterolemia (PMID: 15576851, 19843101, 30876530, 17765246, 16627557, 33231818, 33508743, 20828696, 26020417, 20828696, 33027386). It is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is located in a well-established protein functional domain where other pathogenic variants have been described. It is predicted to be deleterious by in silico analysis. Functional studies suggest that this variant results in a deleterious effect on the protein (PMID: 30617148, 29874871, 1301956). Other missense substitutions at this amino acid residue have been previously reported in individual(s) with hypercholesterolemia (ClinVar IDs: 1755040, 251375, 251374, 251373), which supports the functional importance of this position. (less)
Number of individuals with the variant: 1
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Pathogenic
(Feb 25, 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: SCV002664572.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.D224N pathogenic mutation (also known as c.670G>A), located in coding exon 4 of the LDLR gene, results from a G to A substitution at … (more)
The p.D224N pathogenic mutation (also known as c.670G>A), located in coding exon 4 of the LDLR gene, results from a G to A substitution at nucleotide position 670. The aspartic acid at codon 224 is replaced by asparagine, an amino acid with highly similar properties. This alteration impacts a residue in the conserved cluster of acidic amino acids at the C-terminal end of LDLR class A repeat 5 (Jeon H and Blacklow C. Annu. Rev. Biochem. 2005;74:535-62). This alteration (with legacy nomenclature p.D203N) has been described in the heterozygous and homozygous states in patients with familial hypercholesterolemia (FH), including multiple FH probands from a Portuguese village, three of whom were subsequently shown to be related (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Wang J et al. J. Lipid Res., 2005 Feb;46:366-72; Blesa S et al. Clin. Chem., 2006 Jun;52:1021-5; Bourbon M et al. Atherosclerosis, 2008 Feb;196:633-42; Gaspar IM et al. Atheroscler Suppl, 2019 Mar;36:28-30). This alteration was also reported in the compound heterozygous state in a patient with severe FH and in a heterozygous state in the proband's affected daughter (Medeiros AM et al. Atherosclerosis, 2010 Oct;212:553-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Functional studies suggest this alteration causes reduced LDLR activity (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Deng SJ et al. J. Lipid Res., 2019 Jan;epub ahead of print). Other alterations affecting the same amino acid, p.D224A, p.D224G, and p.D224V, have also been reported in association with FH (Loubser O et al. Clin. Genet., 1999 May;55:340-5; Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Giesel J et al. Hum. Genet., 1995 Sep;96:301-4). Based on the majority of available evidence to date, this variant is interpreted as a disease-causing mutation. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
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Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum
Accession: SCV000606193.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
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Pathogenic
(Oct 05, 1986)
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no assertion criteria provided
Method: literature only
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FH PORTUGAL
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000024061.3
First in ClinVar: Apr 04, 2013 Last updated: Jun 23, 2019 |
Comment on evidence:
In Portuguese patients with FH (FHCL1; 143890), Hobbs et al. (1992) identified a G-A transition in exon 4 of the LDLR gene, resulting in an … (more)
In Portuguese patients with FH (FHCL1; 143890), Hobbs et al. (1992) identified a G-A transition in exon 4 of the LDLR gene, resulting in an asp203-to-asn (D203N) substitution. The mutation was not found in over 200 non-FH alleles. (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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Comparison of the mutation spectrum and association with pre and post treatment lipid measures of children with heterozygous familial hypercholesterolaemia (FH) from eight European countries. | Futema M | Atherosclerosis | 2021 | PMID: 33508743 |
Cascade screening and genetic diagnosis of familial hypercholesterolemia in clusters of the Southeastern region from Brazil. | de Paiva Silvino JP | Molecular biology reports | 2020 | PMID: 33231818 |
Compound Heterozygous Familial Hypercholesterolemia Caused by LDLR Variants. | Pamplona-Cunha H | Arquivos brasileiros de cardiologia | 2020 | PMID: 33027386 |
Variable expression and penetrance in Portuguese families with Familial Hypercholesterolemia with mild phenotype. | Gaspar IM | Atherosclerosis. Supplements | 2019 | PMID: 30876530 |
Identification of amino acid residues in the ligand binding repeats of LDL receptor important for PCSK9 binding. | Deng SJ | Journal of lipid research | 2019 | PMID: 30617148 |
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 |
Mutational analysis of a cohort with clinical diagnosis of familial hypercholesterolemia: considerations for genetic diagnosis improvement. | Medeiros AM | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26020417 |
Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. | Bertolini S | Atherosclerosis | 2013 | PMID: 23375686 |
Update of the Portuguese Familial Hypercholesterolaemia Study. | Medeiros AM | Atherosclerosis | 2010 | PMID: 20828696 |
Mutation screening in patients for familial hypercholesterolaemia (ADH). | Taylor A | Clinical genetics | 2010 | PMID: 19843101 |
Familial hypercholesterolaemia in Portugal. | Bourbon M | Atherosclerosis | 2008 | PMID: 17765246 |
Multiplex ARMS analysis to detect 13 common mutations in familial hypercholesterolaemia. | Taylor A | Clinical genetics | 2007 | PMID: 17539906 |
Analysis of sequence variations in the LDL receptor gene in Spain: general gene screening or search for specific alterations? | Blesa S | Clinical chemistry | 2006 | PMID: 16627557 |
Multiplex ligation-dependent probe amplification of LDLR enhances molecular diagnosis of familial hypercholesterolemia. | Wang J | Journal of lipid research | 2005 | PMID: 15576851 |
Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. | Hobbs HH | Human mutation | 1992 | PMID: 1301956 |
Deletion of exon encoding cysteine-rich repeat of low density lipoprotein receptor alters its binding specificity in a subject with familial hypercholesterolemia. | Hobbs HH | The Journal of biological chemistry | 1986 | PMID: 3020025 |
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Text-mined citations for rs387906303 ...
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.