subjects mutated among 2600 FH index cases screened = 2 / in association with c.1765G>A, p.Asp589Asn / Software predictions: Benign
ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.769C>T (p.Arg257Trp)
Germline
Classification
Help
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.
(17)
Help
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.
Conflicting classifications of pathogenicity
Uncertain significance(10); Likely benign(5)
Uncertain significance(10); Likely benign(5)
17
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000527.5(LDLR):c.769C>T (p.Arg257Trp)
Variation ID: 251446 Accession: VCV000251446.36
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19p13.2 19: 11106639 (GRCh38) [ NCBI UCSC ] 19: 11217315 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jul 29, 2016 Jan 19, 2025 Aug 13, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.769C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Arg257Trp missense NM_001195798.2:c.769C>T NP_001182727.1:p.Arg257Trp missense NM_001195799.2:c.646C>T NP_001182728.1:p.Arg216Trp missense NM_001195800.2:c.314-753C>T intron variant NM_001195803.2:c.388C>T NP_001182732.1:p.Arg130Trp missense NC_000019.10:g.11106639C>T NC_000019.9:g.11217315C>T NG_009060.1:g.22259C>T LRG_274:g.22259C>T LRG_274t1:c.769C>T LRG_274p1:p.Arg257Trp P01130:p.Arg257Trp - Protein change
- R257W, R216W, R130W
- Other names
- -
- Canonical SPDI
- NC_000019.10:11106638:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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. |
|||
| LDLR | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
4133 | 4423 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Conflicting classifications of pathogenicity (9) |
criteria provided, conflicting classifications
|
Aug 13, 2024 | RCV000237953.17 | |
| Conflicting classifications of pathogenicity (3) |
criteria provided, conflicting classifications
|
Dec 30, 2023 | RCV000775048.18 | |
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Jul 8, 2024 | RCV000845535.9 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Apr 11, 2024 | RCV002401930.3 | |
| Likely benign (1) |
criteria provided, conflicting classifications
|
Jun 18, 2024 | RCV001800605.5 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
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
Help
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
Help
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
Help
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. |
|
|---|---|---|---|---|---|
|
Likely benign
(Mar 25, 2016)
|
criteria provided, single submitter
Method: literature only
|
Familial hypercholesterolemia
Affected status: yes
Allele origin:
germline
|
LDLR-LOVD, British Heart Foundation
Accession: SCV000294964.2
First in ClinVar: Jul 29, 2016 Last updated: Oct 10, 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
Observation 5:
Number of individuals with the variant: 1
Observation 6:
Number of individuals with the variant: 1
|
|
|
Likely benign
(Dec 16, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
|
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix
Accession: SCV000503232.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Comment:
subjects mutated among 2600 FH index cases screened = 2 / in association with c.1765G>A, p.Asp589Asn / Software predictions: Benign
Number of individuals with the variant: 2
|
|
|
Uncertain significance
(Mar 01, 2016)
|
criteria provided, single submitter
Method: research
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Laboratory of Genetics and Molecular Cardiology, University of São Paulo
Study: HipercolBrasil
Accession: SCV000588517.1 First in ClinVar: Aug 13, 2017 Last updated: Aug 13, 2017 |
Observation 1:
Comment on evidence:
%MAF(ExAC):0.007414
Observation 2:
Comment on evidence:
Assay description:Heterologous cells (CHO), FACS assays
Result:
normal LDLR activity
|
|
|
Uncertain significance
(Mar 01, 2016)
|
criteria provided, single submitter
Method: research
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Fundacion Hipercolesterolemia Familiar
Study: SAFEHEART
Accession: SCV000607499.1 First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
Observation 1:
Comment on evidence:
%MAF(ExAC):0.007414
Observation 2:
Comment on evidence:
Heterologous cells (CHO), FACS assays
Result:
normal LDLR activity
|
|
|
Uncertain significance
(Jan 02, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Robarts Research Institute, Western University
Accession: SCV000782953.1
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
|
|
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Uncertain significance
(-)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000987649.1
First in ClinVar: Sep 08, 2019 Last updated: Sep 08, 2019 |
|
|
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Uncertain significance
(Mar 03, 2019)
|
criteria provided, single submitter
Method: research
|
Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
|
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia
Accession: SCV001432577.1
First in ClinVar: Sep 19, 2020 Last updated: Sep 19, 2020 |
Number of individuals with the variant: 1
Clinical Features:
Dutch Lipid Clinic Network Criteria score (present) , low-density lipoprotein cholesterol level (present)
|
|
|
Likely benign
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille
Accession: SCV000583738.2
First in ClinVar: Jul 29, 2016 Last updated: Feb 04, 2024
Comment:
ACMG Guidelines: Pathogenic (ii)
|
Comment:
This missense variant LDLR:c.769C>T (also known as p.Arg236Trp in the mature protein), replaces a arginine with tryptophan at codon 257 of the LDLR protein (p.Arg257Trp). … (more)
This missense variant LDLR:c.769C>T (also known as p.Arg236Trp in the mature protein), replaces a arginine with tryptophan at codon 257 of the LDLR protein (p.Arg257Trp). 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 reclassified as “Likely Benign” from evidence as follows. It is located within a conserved (REVEL=0.648) functional domain (LDLR Class A6) involved in LDL binding with LDL receptors. Because this variant is observed with a frequency <0.02% in the general population (GnomAD= 0.0000985, no homozygotes) multiple reports classify this variant as VUS (PM2). However, despite apparent cosegregation in several independent FH families, it has been frequently observed in normolipidemic individuals (BS2) or in Cis with other proven pathogenic variants in FH patients (BP2). Finally, several independent level 1 in-vitro functional studies have shown consistently that this variant has a neutral effect on LDLR function (BS3). (less)
Number of individuals with the variant: 1
Clinical Features:
Increased LDL cholesterol concentration (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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Likely benign
(Dec 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000544695.9
First in ClinVar: Jul 29, 2016 Last updated: Feb 14, 2024 |
|
|
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Uncertain significance
(Dec 09, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000909147.5
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant (also known as p.Arg236Trp in the mature protein) is located in the sixth LDLR type A repeat in the ligand binding domain … (more)
This missense variant (also known as p.Arg236Trp in the mature protein) is located in the sixth LDLR type A repeat in the ligand binding domain 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). Functional studies have demonstrated that the variant protein shows normal LDLR expression at the cell surface and normal LDL binding and uptake activity (PMID: 25545329). This variant has been reported in many individuals affected with or suspected of having familial hypercholesterolemia in Brazil, China, Germany, Korea and the Netherlands (PMID: 11462246, 11933210, 16250003, 20538126, 22353362, 25461735, 25962062, 26343872, 32759540, 33994402, 34456200, 34573395, 35137788). In two Chinese brothers with severe hypercholesterolemia, this variant co-occurred with two other heterozygous variants in LDLR (p.Gln191* and p.Asp589Asn) (PMID: 29365890). This variant and p.Asp589Asn have been reported to occur on the same allele (PMID: 16250003, 18325082). This variant has been identified in 26/282894 chromosomes (20/19954 East Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Functional studies and relatively high allele frequency in the general population indicate that this variant is unlikely to cause disease. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
|
|
|
Uncertain significance
(Apr 11, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002669523.3
First in ClinVar: Nov 29, 2022 Last updated: Aug 11, 2024 |
Comment:
The p.R257W variant (also known as c.769C>T), located in coding exon 5 of the LDLR gene, results from a C to T substitution at nucleotide … (more)
The p.R257W variant (also known as c.769C>T), located in coding exon 5 of the LDLR gene, results from a C to T substitution at nucleotide position 769. The arginine at codon 257 is replaced by tryptophan, an amino acid with dissimilar properties. This variant (also referred to as p.R236W) has been previously described in several individuals with familial hypercholesterolemia (FH) from various ethnic backgrounds, often along with the LDLR p.D589N variant (Nauck MS et al. Hum Mutat. 2001;18:165-6; Salazar LA et al. Hum Mutat. 2002;19:462-3; Fouchier SW et al. Hum Mutat. 2005;26:550-6; Chiou KR et al. Am J Cardiol. 2010;105:1752-8; Han SM et al. PLoS ONE. 2015;10:e0126706; Pek SLT et al. Atherosclerosis, 2018 Feb;269:106-116). In functional in vitro analyses, the p.R257W variant has demonstrated similar effects as the wild-type, including low-density lipoprotein receptor (LDLR) expression and the ability to bind and internalize LDL (Etxebarria A et al. Atherosclerosis. 2015;238:304-12). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). 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. (less)
|
|
|
Uncertain significance
(Jul 08, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002004038.3
First in ClinVar: Nov 06, 2021 Last updated: Sep 16, 2024 |
Comment:
Observed in multiple unrelated patients from different ethnic backgrounds with familial hypercholesterolemia (FH) in the published literature (PMID: 26690388, 32759540, 11462246, 11933210, 16250003, 19318025, 20538126, … (more)
Observed in multiple unrelated patients from different ethnic backgrounds with familial hypercholesterolemia (FH) in the published literature (PMID: 26690388, 32759540, 11462246, 11933210, 16250003, 19318025, 20538126, 25962062, 25461735, 26343872, 26875521, 29353225, 30526649, 30293936, 30592178, 34573395); Many individuals with p.R257W in the published literature harbor a second variant in LDLR (p.D589N) in cis, including two individuals homozygous for both variants; these variants are suspected to be linked on the same allele (PMID: 16250003, 20538126, 25962062, 29399563, 30795984, 33994402); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(R236W); This variant is associated with the following publications: (PMID: 30592178, 29083407, 29353225, 30526649, 30293936, 11462246, 20538126, 26332594, 11933210, 25461735, 25962062, 26343872, 19318025, 26875521, 22353362, 25545329, 16250003, 32041611, 32719484, 35538921, 30400955, 29399563, 35999587, 18325082, 35560019, 26690388, 32759540, 34573395, 30795984, 33994402, 34456200) (less)
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Likely benign
(Jun 18, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003844390.2
First in ClinVar: Mar 26, 2023 Last updated: Sep 16, 2024 |
Comment:
Variant summary: LDLR c.769C>T (p.Arg257Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: LDLR c.769C>T (p.Arg257Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.5e-05 in 251486 control chromosomes, predominantly at a frequency of 0.00098 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (9.5e-05 vs 0.0013), allowing no conclusion about variant significance. c.769C>T has been reported in the literature in individuals affected with Familial Hypercholesterolemia without strong evidence of causality (e.g. Luirink_2019, Huang_2022, Kim_2022). 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. These results showed no damaging effect of this variant (Etxebarria_2015). The following publications have been ascertained in the context of this evaluation (PMID: 25545329, 30795984, 34456200, 33994402). ClinVar contains an entry for this variant (Variation ID: 251446). Based on the evidence outlined above, the variant was classified as likely benign. (less)
|
|
|
Uncertain Significance
(Aug 13, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
(Semidominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004820210.2
First in ClinVar: Apr 20, 2024 Last updated: Dec 14, 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)
|
Comment:
This missense variant (also known as p.Arg236Trp in the mature protein) is located in the sixth LDLR type A repeat in the ligand binding domain … (more)
This missense variant (also known as p.Arg236Trp in the mature protein) is located in the sixth LDLR type A repeat in the ligand binding domain 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). Functional studies have demonstrated that the variant protein shows normal LDLR expression at the cell surface and normal LDL binding and uptake activity (PMID: 25545329). This variant has been reported in many individuals affected with or suspected of having familial hypercholesterolemia in Brazil, China, Germany, Korea and the Netherlands (PMID: 11462246, 11933210, 16250003, 20538126, 22353362, 25461735, 25962062, 26343872, 32759540, 33994402, 34456200, 34573395, 35137788). In two Chinese brothers with severe hypercholesterolemia, this variant co-occurred with two other heterozygous variants in LDLR (p.Gln191* and p.Asp589Asn) (PMID: 29399563). This variant and p.Asp589Asn have been reported to occur on the same allele (PMID: 16250003, 18325082). This variant has been identified in 26/282894 chromosomes (20/19954 East Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Functional studies and relatively high allele frequency in the general population indicate that this variant is unlikely to cause disease. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 12
Zygosity: Single Heterozygote
|
|
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Uncertain significance
(Oct 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002047051.2
First in ClinVar: Jan 03, 2022 Last updated: Jan 19, 2025 |
Comment:
The LDLR c.769C>T (p.Arg257Trp) variant (also known as R257W and R236W) has been reported in the published literature in multiple individuals affected with hypercholesterolemia (PMIDs: … (more)
The LDLR c.769C>T (p.Arg257Trp) variant (also known as R257W and R236W) has been reported in the published literature in multiple individuals affected with hypercholesterolemia (PMIDs: 11462246 (2001), 11933210 (2002), 19318025 (2009), 22353362 (2012), 25461735 (2015), 29353225 (2018), 29399563 (2018), 30293936 (2018), 31345425 (2019), 32759540 (2020), 34573395 (2021), 35137788 (2022)). In addition, this variant is often seen together with another LDLR variant, c.1765G>A (p.Asp589Asn). When this complex allele occurs in the homozygous phase or in trans with other deleterious LDLR variants, c.986G>A (p.Cys329Tyr) or c.1754T>A (p.Ile585Asn), the phenotype appears more severe and is suggestive of homozygous hypercholesterolemia (HoFH) (PMIDs: 30795984 (2019), 25962062 (2015), 20538126 (2010)). A functional study, however, indicated that the c.769C>T (p.Arg257Trp) variant showed normal levels of LDLR protein expression as well as normal LDL binding and uptake activity (PMID: 25545329 (2015)). Another report described the variant to retain 85% activity (PMID: 27206935 (2016)) and further research is necessary. The frequency of this variant in the general population, 0.0012 (18/14424 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum
Accession: SCV000606221.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
|
|
|
Likely benign
(Oct 08, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002086387.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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Comment:
Comment:
This missense variant LDLR:c.769C>T (also known as p.Arg236Trp in the mature protein), replaces a arginine with tryptophan at codon 257 of the LDLR protein (p.Arg257Trp). 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 reclassified as “Likely Benign” from evidence as follows. It is located within a conserved (REVEL=0.648) functional domain (LDLR Class A6) involved in LDL binding with LDL receptors. Because this variant is observed with a frequency <0.02% in the general population (GnomAD= 0.0000985, no homozygotes) multiple reports classify this variant as VUS (PM2). However, despite apparent cosegregation in several independent FH families, it has been frequently observed in normolipidemic individuals (BS2) or in Cis with other proven pathogenic variants in FH patients (BP2). Finally, several independent level 1 in-vitro functional studies have shown consistently that this variant has a neutral effect on LDLR function (BS3).
Comment:
This missense variant (also known as p.Arg236Trp in the mature protein) is located in the sixth LDLR type A repeat in the ligand binding domain 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). Functional studies have demonstrated that the variant protein shows normal LDLR expression at the cell surface and normal LDL binding and uptake activity (PMID: 25545329). This variant has been reported in many individuals affected with or suspected of having familial hypercholesterolemia in Brazil, China, Germany, Korea and the Netherlands (PMID: 11462246, 11933210, 16250003, 20538126, 22353362, 25461735, 25962062, 26343872, 32759540, 33994402, 34456200, 34573395, 35137788). In two Chinese brothers with severe hypercholesterolemia, this variant co-occurred with two other heterozygous variants in LDLR (p.Gln191* and p.Asp589Asn) (PMID: 29365890). This variant and p.Asp589Asn have been reported to occur on the same allele (PMID: 16250003, 18325082). This variant has been identified in 26/282894 chromosomes (20/19954 East Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Functional studies and relatively high allele frequency in the general population indicate that this variant is unlikely to cause disease. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The p.R257W variant (also known as c.769C>T), located in coding exon 5 of the LDLR gene, results from a C to T substitution at nucleotide position 769. The arginine at codon 257 is replaced by tryptophan, an amino acid with dissimilar properties. This variant (also referred to as p.R236W) has been previously described in several individuals with familial hypercholesterolemia (FH) from various ethnic backgrounds, often along with the LDLR p.D589N variant (Nauck MS et al. Hum Mutat. 2001;18:165-6; Salazar LA et al. Hum Mutat. 2002;19:462-3; Fouchier SW et al. Hum Mutat. 2005;26:550-6; Chiou KR et al. Am J Cardiol. 2010;105:1752-8; Han SM et al. PLoS ONE. 2015;10:e0126706; Pek SLT et al. Atherosclerosis, 2018 Feb;269:106-116). In functional in vitro analyses, the p.R257W variant has demonstrated similar effects as the wild-type, including low-density lipoprotein receptor (LDLR) expression and the ability to bind and internalize LDL (Etxebarria A et al. Atherosclerosis. 2015;238:304-12). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). 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.
Comment:
Observed in multiple unrelated patients from different ethnic backgrounds with familial hypercholesterolemia (FH) in the published literature (PMID: 26690388, 32759540, 11462246, 11933210, 16250003, 19318025, 20538126, 25962062, 25461735, 26343872, 26875521, 29353225, 30526649, 30293936, 30592178, 34573395); Many individuals with p.R257W in the published literature harbor a second variant in LDLR (p.D589N) in cis, including two individuals homozygous for both variants; these variants are suspected to be linked on the same allele (PMID: 16250003, 20538126, 25962062, 29399563, 30795984, 33994402); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(R236W); This variant is associated with the following publications: (PMID: 30592178, 29083407, 29353225, 30526649, 30293936, 11462246, 20538126, 26332594, 11933210, 25461735, 25962062, 26343872, 19318025, 26875521, 22353362, 25545329, 16250003, 32041611, 32719484, 35538921, 30400955, 29399563, 35999587, 18325082, 35560019, 26690388, 32759540, 34573395, 30795984, 33994402, 34456200)
Comment:
Variant summary: LDLR c.769C>T (p.Arg257Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.5e-05 in 251486 control chromosomes, predominantly at a frequency of 0.00098 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (9.5e-05 vs 0.0013), allowing no conclusion about variant significance. c.769C>T has been reported in the literature in individuals affected with Familial Hypercholesterolemia without strong evidence of causality (e.g. Luirink_2019, Huang_2022, Kim_2022). 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. These results showed no damaging effect of this variant (Etxebarria_2015). The following publications have been ascertained in the context of this evaluation (PMID: 25545329, 30795984, 34456200, 33994402). ClinVar contains an entry for this variant (Variation ID: 251446). Based on the evidence outlined above, the variant was classified as likely benign.
Comment:
This missense variant (also known as p.Arg236Trp in the mature protein) is located in the sixth LDLR type A repeat in the ligand binding domain 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). Functional studies have demonstrated that the variant protein shows normal LDLR expression at the cell surface and normal LDL binding and uptake activity (PMID: 25545329). This variant has been reported in many individuals affected with or suspected of having familial hypercholesterolemia in Brazil, China, Germany, Korea and the Netherlands (PMID: 11462246, 11933210, 16250003, 20538126, 22353362, 25461735, 25962062, 26343872, 32759540, 33994402, 34456200, 34573395, 35137788). In two Chinese brothers with severe hypercholesterolemia, this variant co-occurred with two other heterozygous variants in LDLR (p.Gln191* and p.Asp589Asn) (PMID: 29399563). This variant and p.Asp589Asn have been reported to occur on the same allele (PMID: 16250003, 18325082). This variant has been identified in 26/282894 chromosomes (20/19954 East Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Functional studies and relatively high allele frequency in the general population indicate that this variant is unlikely to cause disease. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The LDLR c.769C>T (p.Arg257Trp) variant (also known as R257W and R236W) has been reported in the published literature in multiple individuals affected with hypercholesterolemia (PMIDs: 11462246 (2001), 11933210 (2002), 19318025 (2009), 22353362 (2012), 25461735 (2015), 29353225 (2018), 29399563 (2018), 30293936 (2018), 31345425 (2019), 32759540 (2020), 34573395 (2021), 35137788 (2022)). In addition, this variant is often seen together with another LDLR variant, c.1765G>A (p.Asp589Asn). When this complex allele occurs in the homozygous phase or in trans with other deleterious LDLR variants, c.986G>A (p.Cys329Tyr) or c.1754T>A (p.Ile585Asn), the phenotype appears more severe and is suggestive of homozygous hypercholesterolemia (HoFH) (PMIDs: 30795984 (2019), 25962062 (2015), 20538126 (2010)). A functional study, however, indicated that the c.769C>T (p.Arg257Trp) variant showed normal levels of LDLR protein expression as well as normal LDL binding and uptake activity (PMID: 25545329 (2015)). Another report described the variant to retain 85% activity (PMID: 27206935 (2016)) and further research is necessary. The frequency of this variant in the general population, 0.0012 (18/14424 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
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. |
Comment:
subjects mutated among 2600 FH index cases screened = 2 / in association with c.1765G>A, p.Asp589Asn / Software predictions: Benign
Comment:
This missense variant LDLR:c.769C>T (also known as p.Arg236Trp in the mature protein), replaces a arginine with tryptophan at codon 257 of the LDLR protein (p.Arg257Trp). 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 reclassified as “Likely Benign” from evidence as follows. It is located within a conserved (REVEL=0.648) functional domain (LDLR Class A6) involved in LDL binding with LDL receptors. Because this variant is observed with a frequency <0.02% in the general population (GnomAD= 0.0000985, no homozygotes) multiple reports classify this variant as VUS (PM2). However, despite apparent cosegregation in several independent FH families, it has been frequently observed in normolipidemic individuals (BS2) or in Cis with other proven pathogenic variants in FH patients (BP2). Finally, several independent level 1 in-vitro functional studies have shown consistently that this variant has a neutral effect on LDLR function (BS3).
Comment:
This missense variant (also known as p.Arg236Trp in the mature protein) is located in the sixth LDLR type A repeat in the ligand binding domain 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). Functional studies have demonstrated that the variant protein shows normal LDLR expression at the cell surface and normal LDL binding and uptake activity (PMID: 25545329). This variant has been reported in many individuals affected with or suspected of having familial hypercholesterolemia in Brazil, China, Germany, Korea and the Netherlands (PMID: 11462246, 11933210, 16250003, 20538126, 22353362, 25461735, 25962062, 26343872, 32759540, 33994402, 34456200, 34573395, 35137788). In two Chinese brothers with severe hypercholesterolemia, this variant co-occurred with two other heterozygous variants in LDLR (p.Gln191* and p.Asp589Asn) (PMID: 29365890). This variant and p.Asp589Asn have been reported to occur on the same allele (PMID: 16250003, 18325082). This variant has been identified in 26/282894 chromosomes (20/19954 East Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Functional studies and relatively high allele frequency in the general population indicate that this variant is unlikely to cause disease. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The p.R257W variant (also known as c.769C>T), located in coding exon 5 of the LDLR gene, results from a C to T substitution at nucleotide position 769. The arginine at codon 257 is replaced by tryptophan, an amino acid with dissimilar properties. This variant (also referred to as p.R236W) has been previously described in several individuals with familial hypercholesterolemia (FH) from various ethnic backgrounds, often along with the LDLR p.D589N variant (Nauck MS et al. Hum Mutat. 2001;18:165-6; Salazar LA et al. Hum Mutat. 2002;19:462-3; Fouchier SW et al. Hum Mutat. 2005;26:550-6; Chiou KR et al. Am J Cardiol. 2010;105:1752-8; Han SM et al. PLoS ONE. 2015;10:e0126706; Pek SLT et al. Atherosclerosis, 2018 Feb;269:106-116). In functional in vitro analyses, the p.R257W variant has demonstrated similar effects as the wild-type, including low-density lipoprotein receptor (LDLR) expression and the ability to bind and internalize LDL (Etxebarria A et al. Atherosclerosis. 2015;238:304-12). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). 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.
Comment:
Observed in multiple unrelated patients from different ethnic backgrounds with familial hypercholesterolemia (FH) in the published literature (PMID: 26690388, 32759540, 11462246, 11933210, 16250003, 19318025, 20538126, 25962062, 25461735, 26343872, 26875521, 29353225, 30526649, 30293936, 30592178, 34573395); Many individuals with p.R257W in the published literature harbor a second variant in LDLR (p.D589N) in cis, including two individuals homozygous for both variants; these variants are suspected to be linked on the same allele (PMID: 16250003, 20538126, 25962062, 29399563, 30795984, 33994402); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(R236W); This variant is associated with the following publications: (PMID: 30592178, 29083407, 29353225, 30526649, 30293936, 11462246, 20538126, 26332594, 11933210, 25461735, 25962062, 26343872, 19318025, 26875521, 22353362, 25545329, 16250003, 32041611, 32719484, 35538921, 30400955, 29399563, 35999587, 18325082, 35560019, 26690388, 32759540, 34573395, 30795984, 33994402, 34456200)
Comment:
Variant summary: LDLR c.769C>T (p.Arg257Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.5e-05 in 251486 control chromosomes, predominantly at a frequency of 0.00098 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (9.5e-05 vs 0.0013), allowing no conclusion about variant significance. c.769C>T has been reported in the literature in individuals affected with Familial Hypercholesterolemia without strong evidence of causality (e.g. Luirink_2019, Huang_2022, Kim_2022). 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. These results showed no damaging effect of this variant (Etxebarria_2015). The following publications have been ascertained in the context of this evaluation (PMID: 25545329, 30795984, 34456200, 33994402). ClinVar contains an entry for this variant (Variation ID: 251446). Based on the evidence outlined above, the variant was classified as likely benign.
Comment:
This missense variant (also known as p.Arg236Trp in the mature protein) is located in the sixth LDLR type A repeat in the ligand binding domain 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). Functional studies have demonstrated that the variant protein shows normal LDLR expression at the cell surface and normal LDL binding and uptake activity (PMID: 25545329). This variant has been reported in many individuals affected with or suspected of having familial hypercholesterolemia in Brazil, China, Germany, Korea and the Netherlands (PMID: 11462246, 11933210, 16250003, 20538126, 22353362, 25461735, 25962062, 26343872, 32759540, 33994402, 34456200, 34573395, 35137788). In two Chinese brothers with severe hypercholesterolemia, this variant co-occurred with two other heterozygous variants in LDLR (p.Gln191* and p.Asp589Asn) (PMID: 29399563). This variant and p.Asp589Asn have been reported to occur on the same allele (PMID: 16250003, 18325082). This variant has been identified in 26/282894 chromosomes (20/19954 East Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Functional studies and relatively high allele frequency in the general population indicate that this variant is unlikely to cause disease. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The LDLR c.769C>T (p.Arg257Trp) variant (also known as R257W and R236W) has been reported in the published literature in multiple individuals affected with hypercholesterolemia (PMIDs: 11462246 (2001), 11933210 (2002), 19318025 (2009), 22353362 (2012), 25461735 (2015), 29353225 (2018), 29399563 (2018), 30293936 (2018), 31345425 (2019), 32759540 (2020), 34573395 (2021), 35137788 (2022)). In addition, this variant is often seen together with another LDLR variant, c.1765G>A (p.Asp589Asn). When this complex allele occurs in the homozygous phase or in trans with other deleterious LDLR variants, c.986G>A (p.Cys329Tyr) or c.1754T>A (p.Ile585Asn), the phenotype appears more severe and is suggestive of homozygous hypercholesterolemia (HoFH) (PMIDs: 30795984 (2019), 25962062 (2015), 20538126 (2010)). A functional study, however, indicated that the c.769C>T (p.Arg257Trp) variant showed normal levels of LDLR protein expression as well as normal LDL binding and uptake activity (PMID: 25545329 (2015)). Another report described the variant to retain 85% activity (PMID: 27206935 (2016)) and further research is necessary. The frequency of this variant in the general population, 0.0012 (18/14424 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Identification of genetic variants related to metabolic syndrome by next-generation sequencing. | Lee S | Diabetology & metabolic syndrome | 2022 | PMID: 35999587 |
| 2022 Consensus statement on the management of familial hypercholesterolemia in Korea. | Lee CJ | The Korean journal of internal medicine | 2022 | PMID: 35882565 |
| Screening for Familial Hypercholesterolemia in Small Towns: Experience from 11 Brazilian Towns in the Hipercolbrasil Program. | Jannes CE | Arquivos brasileiros de cardiologia | 2022 | PMID: 35137788 |
| The Clinical Genome Resource (ClinGen) Familial Hypercholesterolemia Variant Curation Expert Panel consensus guidelines for LDLR variant classification. | Chora JR | Genetics in medicine : official journal of the American College of Medical Genetics | 2022 | PMID: 34906454 |
| Phenotypic and Genetic Analyses of Korean Patients with Familial Hypercholesterolemia: Results from the KFH Registry 2020. | Kim H | Journal of atherosclerosis and thrombosis | 2022 | PMID: 34456200 |
| Genetic Analysis in a Taiwanese Cohort of 750 Index Patients with Clinically Diagnosed Familial Hypercholesterolemia. | Huang CC | Journal of atherosclerosis and thrombosis | 2022 | PMID: 33994402 |
| Familial Hypercholesterolemia Genetic Variations and Long-Term Cardiovascular Outcomes in Patients with Hypercholesterolemia Who Underwent Coronary Angiography. | Lee WJ | Genes | 2021 | PMID: 34573395 |
| Targeted Genetic Analysis in a Chinese Cohort of 208 Patients Related to Familial Hypercholesterolemia. | Wang H | Journal of atherosclerosis and thrombosis | 2020 | PMID: 32759540 |
| Population genetic screening efficiently identifies carriers of autosomal dominant diseases. | Grzymski JJ | Nature medicine | 2020 | PMID: 32719484 |
| Six years' experience with LipidSeq: clinical and research learnings from a hybrid, targeted sequencing panel for dyslipidemias. | Dron JS | BMC medical genomics | 2020 | PMID: 32041611 |
| Risk of Premature Atherosclerotic Disease in Patients With Monogenic Versus Polygenic Familial Hypercholesterolemia. | Trinder M | Journal of the American College of Cardiology | 2019 | PMID: 31345425 |
| The clinical and molecular diversity of homozygous familial hypercholesterolemia in children: Results from the GeneTics of clinical homozygous hypercholesterolemia (GoTCHA) study. | Luirink IK | Journal of clinical lipidology | 2019 | PMID: 30795984 |
| Genetic variations in familial hypercholesterolemia and cascade screening in East Asians. | Chan ML | Molecular genetics & genomic medicine | 2019 | PMID: 30592178 |
| Application of expanded genetic analysis in the diagnosis of familial hypercholesterolemia in patients with very early-onset coronary artery disease. | Cao YX | Journal of translational medicine | 2018 | PMID: 30526649 |
| Genetic basis of index patients with familial hypercholesterolemia in Chinese population: mutation spectrum and genotype-phenotype correlation. | Sun D | Lipids in health and disease | 2018 | PMID: 30400955 |
| Autosomal dominant hypercholesterolemia in Catalonia: Correspondence between clinical-biochemical and genetic diagnostics in 967 patients studied in a multicenter clinical setting. | Martín-Campos JM | Journal of clinical lipidology | 2018 | PMID: 30293936 |
| Detection of Familial Hypercholesterolemia Using Next Generation Sequencing in Two Population-Based Cohorts. | Kim HN | Chonnam medical journal | 2018 | PMID: 29399563 |
| Spectrum of mutations in index patients with familial hypercholesterolemia in Singapore: Single center study. | Pek SLT | Atherosclerosis | 2018 | PMID: 29353225 |
| Evaluation of reported pathogenic variants and their frequencies in a Japanese population based on a whole-genome reference panel of 2049 individuals. | Yamaguchi-Kabata Y | Journal of human genetics | 2018 | PMID: 29192238 |
| Detection of common sequence variations of familial hypercholesterolemia in Taiwan using DNA mass spectrometry. | Chiou KR | Journal of clinical lipidology | 2017 | PMID: 28502495 |
| Exome-wide association analysis reveals novel coding sequence variants associated with lipid traits in Chinese. | Tang CS | Nature communications | 2015 | PMID: 26690388 |
| Clinical features of familial hypercholesterolemia in Korea: Predictors of pathogenic mutations and coronary artery disease - A study supported by the Korean Society of Lipidology and Atherosclerosis. | Shin DG | Atherosclerosis | 2015 | PMID: 26343872 |
| Genetic testing of Korean familial hypercholesterolemia using whole-exome sequencing. | Han SM | PloS one | 2015 | PMID: 25962062 |
| Activity-associated effect of LDL receptor missense variants located in the cysteine-rich repeats. | Etxebarria A | Atherosclerosis | 2015 | PMID: 25545329 |
| Familial hypercholesterolemia in Brazil: cascade screening program, clinical and genetic aspects. | Jannes CE | Atherosclerosis | 2015 | PMID: 25461735 |
| Common mutations of familial hypercholesterolemia patients in Taiwan: characteristics and implications of migrations from southeast China. | Chiou KR | Gene | 2012 | PMID: 22353362 |
| Detection of mutations and large rearrangements of the low-density lipoprotein receptor gene in Taiwanese patients with familial hypercholesterolemia. | Chiou KR | The American journal of cardiology | 2010 | PMID: 20538126 |
| Genetic diagnosis of familial hypercholesterolemia using a DNA-array based platform. | Alonso R | Clinical biochemistry | 2009 | PMID: 19318025 |
| Update and analysis of the University College London low density lipoprotein receptor familial hypercholesterolemia database. | Leigh SE | Annals of human genetics | 2008 | PMID: 18325082 |
| Update of the molecular basis of familial hypercholesterolemia in The Netherlands. | Fouchier SW | Human mutation | 2005 | PMID: 16250003 |
| Molecular basis of familial hypercholesterolemia in Brazil: Identification of seven novel LDLR gene mutations. | Salazar LA | Human mutation | 2002 | PMID: 11933210 |
| Identification of recurrent and novel mutations in the LDL receptor gene in German patients with familial hypercholesterolemia. | Nauck MS | Human mutation | 2001 | PMID: 11462246 |
| A double mutant LDL receptor allele in a cypriot family with heterozygous familial hypercholesterolemia. | Kotze MJ | Human genetics | 1997 | PMID: 9225977 |
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Text-mined citations for this variant ...
HelpRecord last updated Jan 19, 2025
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.