The NM_000527.5(LDLR):c.846C>A (p.Phe282Leu) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PS3_Supporting, PS4_Supporting, PM2, PP3, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PS3_Supporting: Level 3 assays: PMID 25647241: HeLa cells, In vitro microscopy assays - result - 66% wild type LDLR expression (below 70%, Figure 3). ---- functional study is consistent with damaging effect. So, PS3_Supporting is met. PS4_Supporting: Variants meets PM2 and is identified in 2 cases from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille with diagnosis of probable FH based on DLCN criteria. So, PS4_Supporting is met. PM2: PopMax MAF = 0.00001 (0.001%) in European (Non-Finnish) exomes (gnomAD v2.1.1). So, PM2 is met. PP3: REVEL=0.877. It is above 0.75, so PP3 is met. PP4: Variant meets PM2 and is identified in 2 unrelated index cases who fulfill clinical criteria for FH (see PS4 for details), after alternative causes for high cholesterol were excluded.
ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.846C>A (p.Phe282Leu)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Likely pathogenic
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000527.5(LDLR):c.846C>A (p.Phe282Leu)
Variation ID: 183098 Accession: VCV000183098.28
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19p13.2 19: 11107420 (GRCh38) [ NCBI UCSC ] 19: 11218096 (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 Feb 28, 2015 Oct 20, 2024 Apr 28, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.846C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Phe282Leu missense NM_001195798.2:c.846C>A NP_001182727.1:p.Phe282Leu missense NM_001195799.2:c.723C>A NP_001182728.1:p.Phe241Leu missense NM_001195800.2:c.342C>A NP_001182729.1:p.Phe114Leu missense NM_001195803.2:c.465C>A NP_001182732.1:p.Phe155Leu missense NC_000019.10:g.11107420C>A NC_000019.9:g.11218096C>A NG_009060.1:g.23040C>A LRG_274:g.23040C>A LRG_274t1:c.846C>A LRG_274p1:p.Phe282Leu - Protein change
- F282L, F114L, F155L, F241L
- Other names
-
NM_000527.5(LDLR):c.846C>A
- Canonical SPDI
- NC_000019.10:11107419:C:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
functional variant; Sequence Ontology [ SO:0001536]disruptive missense [submitted by Dept. of Genetics and Pharmacogenomics, Merck Research Labs]
-
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.
-
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
- 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 |
4085 | 4361 | |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Dec 19, 2022 | RCV000161969.18 | |
| Likely pathogenic (9) |
reviewed by expert panel
|
Apr 28, 2023 | RCV000238570.14 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Mar 11, 2020 | RCV002444669.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 24, 2023 | RCV003741152.2 |
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 pathogenic
(Apr 28, 2023)
|
reviewed by expert panel
Method: curation
|
Hypercholesterolemia, familial, 1
(Semidominant inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV004022435.1 First in ClinVar: Aug 05, 2023 Last updated: Aug 05, 2023 |
Comment:
The NM_000527.5(LDLR):c.846C>A (p.Phe282Leu) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PS3_Supporting, PS4_Supporting, PM2, PP3, and PP4 as defined by … (more)
The NM_000527.5(LDLR):c.846C>A (p.Phe282Leu) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PS3_Supporting, PS4_Supporting, PM2, PP3, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PS3_Supporting: Level 3 assays: PMID 25647241: HeLa cells, In vitro microscopy assays - result - 66% wild type LDLR expression (below 70%, Figure 3). ---- functional study is consistent with damaging effect. So, PS3_Supporting is met. PS4_Supporting: Variants meets PM2 and is identified in 2 cases from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille with diagnosis of probable FH based on DLCN criteria. So, PS4_Supporting is met. PM2: PopMax MAF = 0.00001 (0.001%) in European (Non-Finnish) exomes (gnomAD v2.1.1). So, PM2 is met. PP3: REVEL=0.877. It is above 0.75, so PP3 is met. PP4: Variant meets PM2 and is identified in 2 unrelated index cases who fulfill clinical criteria for FH (see PS4 for details), after alternative causes for high cholesterol were excluded. (less)
|
|
|
Likely pathogenic
(Nov 05, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
inherited
|
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation
Additional submitter:
Centre of Molecular Biology and Gene Therapy, University Hospital Brno
Accession: SCV000540764.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Number of individuals with the variant: 3
Clinical Features:
Hypercholesterolemia (present) , Ischemic stroke (present)
Family history: yes
Age: 26-54 years
Sex: mixed
Ethnicity/Population group: Caucasian
Geographic origin: Czech Republic
Tissue: Whole blood
|
|
|
Pathogenic
(Mar 30, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Familial Hypercholesterolemia
Affected status: yes
Allele origin:
germline
|
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille
Accession: SCV000583748.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016
Comment:
ACMG Guidelines: Pathogenic (ii)
|
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 : Probable FH
Secondary finding: no
|
|
|
Uncertain significance
(Mar 01, 2016)
|
criteria provided, single submitter
Method: research
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Iberoamerican FH Network
Accession: SCV000748089.1
First in ClinVar: May 03, 2018 Last updated: May 03, 2018
Comment:
Variant present in the database from Argentina
|
Comment on evidence:
%MAF(ExAC):0.0008239
|
|
|
Likely pathogenic
(Oct 20, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001934255.1
First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021 |
|
|
|
Likely pathogenic
(Nov 25, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002762299.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
Comment:
Observed in individuals with familial hypercholesterolemia in published literature (Dukov et al., 2011; Do et al., 2015; Corral et al., 2018; Kose et al., 2020; … (more)
Observed in individuals with familial hypercholesterolemia in published literature (Dukov et al., 2011; Do et al., 2015; Corral et al., 2018; Kose et al., 2020; Leren et al., 2021; Noto et al., 2022); Published functional studies demonstrate a damaging effect with reduced LDL-uptake (Thormaehlen et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25647241, 22698793, 21310417, 30270055, 26666465, 25487149, 32829317, 23833242, 33740630, 35339733) (less)
|
|
|
Uncertain significance
(Mar 11, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002677490.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.F282L variant (also known as c.846C>A), located in coding exon 6 of the LDLR gene, results from a C to A substitution at nucleotide … (more)
The p.F282L variant (also known as c.846C>A), located in coding exon 6 of the LDLR gene, results from a C to A substitution at nucleotide position 846. The phenylalanine at codon 282 is replaced by leucine, an amino acid with highly similar properties, and is located in the ligand binding domain. This variant has been reported in hypercholesterolemia cohorts; however, clinical details were limited (Dušková L et al. Atherosclerosis, 2011 May;216:139-45; Tichý L et al. Atherosclerosis, 2012 Aug;223:401-8; Galaska R et al. J. Atheroscler. Thromb., 2016 May;23:588-95). This variant was also detected in an individual with history of myocardial infarction who had normal LDL-C levels, and limited functional studies suggested some impact on LDL uptake (Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855; Do R et al. Nature, 2015 Feb;518:102-6). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
|
|
Pathogenic
(Dec 19, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005198649.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
|
Likely pathogenic
(Mar 25, 2016)
|
criteria provided, single submitter
Method: literature only
|
Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
LDLR-LOVD, British Heart Foundation
Accession: SCV000295007.2
First in ClinVar: Jul 29, 2016 Last updated: May 03, 2018 |
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(May 27, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV002764774.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Number of individuals with the variant: 1
Clinical Features:
Dyskinesia (present) , Microcephaly (present) , Cerebellar vermis hypoplasia (present) , Global developmental delay (present) , Hypotonia (present) , Hepatosplenomegaly (present)
|
|
|
Pathogenic
(Jun 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004457930.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 183098). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that … (more)
ClinVar contains an entry for this variant (Variation ID: 183098). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LDLR function (PMID: 25647241). 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. This missense change has been observed in individuals with hypercholesterolemia (PMID: 21310417, 30270055, 30592719, 33740630, 35339733). This variant is present in population databases (rs730882090, gnomAD 0.0009%). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 282 of the LDLR protein (p.Phe282Leu). (less)
|
|
|
Likely Pathogenic
(Dec 15, 2023)
|
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: SCV004842746.1
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)
|
Comment:
This variant has been reported in multiple individuals with familial hypercholesterolemia (PMID: 34182004, 30592719, 22698793, 26666465, 29870584, 30270055, 35910211). Functional studies suggest that this variant … (more)
This variant has been reported in multiple individuals with familial hypercholesterolemia (PMID: 34182004, 30592719, 22698793, 26666465, 29870584, 30270055, 35910211). Functional studies suggest that this variant results in a deleterious effect to the protein that is sufficient to be disease-causing (PMID: 25647241). This variant is present in 1/251430 total alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is predicted to be deleterious by in silico analysis. (less)
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(Nov 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002822507.14
First in ClinVar: Jan 21, 2023 Last updated: Oct 20, 2024 |
Comment:
LDLR: PM2, PS3:Moderate, PS4:Moderate
Number of individuals with the variant: 1
|
|
|
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: SCV000606246.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
|
|
|
not provided
(-)
|
no classification provided
(in vitro)
Method: in vitro
|
not provided
Affected status: not applicable
Allele origin:
not applicable
|
Dept. of Genetics and Pharmacogenomics, Merck Research Labs
Accession: SCV000189544.1
First in ClinVar: Feb 28, 2015 Last updated: Feb 28, 2015
Comment:
In vitro functional profiling of LDL-receptor missense alleles identified through large-scale association testing
|
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
Observed in individuals with familial hypercholesterolemia in published literature (Dukov et al., 2011; Do et al., 2015; Corral et al., 2018; Kose et al., 2020; Leren et al., 2021; Noto et al., 2022); Published functional studies demonstrate a damaging effect with reduced LDL-uptake (Thormaehlen et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25647241, 22698793, 21310417, 30270055, 26666465, 25487149, 32829317, 23833242, 33740630, 35339733)
Comment:
The p.F282L variant (also known as c.846C>A), located in coding exon 6 of the LDLR gene, results from a C to A substitution at nucleotide position 846. The phenylalanine at codon 282 is replaced by leucine, an amino acid with highly similar properties, and is located in the ligand binding domain. This variant has been reported in hypercholesterolemia cohorts; however, clinical details were limited (Dušková L et al. Atherosclerosis, 2011 May;216:139-45; Tichý L et al. Atherosclerosis, 2012 Aug;223:401-8; Galaska R et al. J. Atheroscler. Thromb., 2016 May;23:588-95). This variant was also detected in an individual with history of myocardial infarction who had normal LDL-C levels, and limited functional studies suggested some impact on LDL uptake (Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855; Do R et al. Nature, 2015 Feb;518:102-6). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
ClinVar contains an entry for this variant (Variation ID: 183098). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LDLR function (PMID: 25647241). 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. This missense change has been observed in individuals with hypercholesterolemia (PMID: 21310417, 30270055, 30592719, 33740630, 35339733). This variant is present in population databases (rs730882090, gnomAD 0.0009%). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 282 of the LDLR protein (p.Phe282Leu).
Comment:
This variant has been reported in multiple individuals with familial hypercholesterolemia (PMID: 34182004, 30592719, 22698793, 26666465, 29870584, 30270055, 35910211). Functional studies suggest that this variant results in a deleterious effect to the protein that is sufficient to be disease-causing (PMID: 25647241). This variant is present in 1/251430 total alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is predicted to be deleterious by in silico analysis.
Comment:
LDLR: PM2, PS3:Moderate, PS4:Moderate
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|---|---|---|---|
|
has functional consequence
|
|
|
Dept. of Genetics and Pharmacogenomics, Merck Research Labs
Accession: SCV000189544.1
|
Comment:
disruptive missense
|
Comment:
The NM_000527.5(LDLR):c.846C>A (p.Phe282Leu) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PS3_Supporting, PS4_Supporting, PM2, PP3, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PS3_Supporting: Level 3 assays: PMID 25647241: HeLa cells, In vitro microscopy assays - result - 66% wild type LDLR expression (below 70%, Figure 3). ---- functional study is consistent with damaging effect. So, PS3_Supporting is met. PS4_Supporting: Variants meets PM2 and is identified in 2 cases from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille with diagnosis of probable FH based on DLCN criteria. So, PS4_Supporting is met. PM2: PopMax MAF = 0.00001 (0.001%) in European (Non-Finnish) exomes (gnomAD v2.1.1). So, PM2 is met. PP3: REVEL=0.877. It is above 0.75, so PP3 is met. PP4: Variant meets PM2 and is identified in 2 unrelated index cases who fulfill clinical criteria for FH (see PS4 for details), after alternative causes for high cholesterol were excluded.
Comment:
Observed in individuals with familial hypercholesterolemia in published literature (Dukov et al., 2011; Do et al., 2015; Corral et al., 2018; Kose et al., 2020; Leren et al., 2021; Noto et al., 2022); Published functional studies demonstrate a damaging effect with reduced LDL-uptake (Thormaehlen et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25647241, 22698793, 21310417, 30270055, 26666465, 25487149, 32829317, 23833242, 33740630, 35339733)
Comment:
The p.F282L variant (also known as c.846C>A), located in coding exon 6 of the LDLR gene, results from a C to A substitution at nucleotide position 846. The phenylalanine at codon 282 is replaced by leucine, an amino acid with highly similar properties, and is located in the ligand binding domain. This variant has been reported in hypercholesterolemia cohorts; however, clinical details were limited (Dušková L et al. Atherosclerosis, 2011 May;216:139-45; Tichý L et al. Atherosclerosis, 2012 Aug;223:401-8; Galaska R et al. J. Atheroscler. Thromb., 2016 May;23:588-95). This variant was also detected in an individual with history of myocardial infarction who had normal LDL-C levels, and limited functional studies suggested some impact on LDL uptake (Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855; Do R et al. Nature, 2015 Feb;518:102-6). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
ClinVar contains an entry for this variant (Variation ID: 183098). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LDLR function (PMID: 25647241). 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. This missense change has been observed in individuals with hypercholesterolemia (PMID: 21310417, 30270055, 30592719, 33740630, 35339733). This variant is present in population databases (rs730882090, gnomAD 0.0009%). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 282 of the LDLR protein (p.Phe282Leu).
Comment:
This variant has been reported in multiple individuals with familial hypercholesterolemia (PMID: 34182004, 30592719, 22698793, 26666465, 29870584, 30270055, 35910211). Functional studies suggest that this variant results in a deleterious effect to the protein that is sufficient to be disease-causing (PMID: 25647241). This variant is present in 1/251430 total alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is predicted to be deleterious by in silico analysis.
Comment:
LDLR: PM2, PS3:Moderate, PS4:Moderate
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| The Prevalence and Genetic Spectrum of Familial Hypercholesterolemia in Qatar Based on Whole Genome Sequencing of 14,000 Subjects. | Diboun I | Frontiers in genetics | 2022 | PMID: 35910211 |
| Diagnosis of familial hypercholesterolemia in a large cohort of Italian genotyped hypercholesterolemic patients. | Noto D | Atherosclerosis | 2022 | PMID: 35339733 |
| Assessment of microvascular function and pharmacological regulation in genetically confirmed familial hypercholesterolemia. | Pajkowski M | Microvascular research | 2021 | PMID: 34182004 |
| Molecular genetic testing for autosomal dominant hypercholesterolemia in 29,449 Norwegian index patients and 14,230 relatives during the years 1993-2020. | Leren TP | Atherosclerosis | 2021 | PMID: 33740630 |
| Aortic valve calcium score in hypercholesterolemic patients with and without low-density lipoprotein receptor gene mutation. | Gałąska R | PloS one | 2018 | PMID: 30592719 |
| Unusual genetic variants associated with hypercholesterolemia in Argentina. | Corral P | Atherosclerosis | 2018 | PMID: 30270055 |
| Prediction of subtle left ventricular systolic dysfunction in homozygous and heterozygous familial hypercholesterolemia: Genetic analyses and speckle tracking echocardiography study. | Saracoglu E | Echocardiography (Mount Kisco, N.Y.) | 2018 | PMID: 29870584 |
| Assessment of Subclinical Atherosclerosis Using Computed Tomography Calcium Scores in Patients with Familial and Nonfamilial Hypercholesterolemia. | Galaska R | Journal of atherosclerosis and thrombosis | 2016 | PMID: 26666465 |
| Systematic cell-based phenotyping of missense alleles empowers rare variant association studies: a case for LDLR and myocardial infarction. | Thormaehlen AS | PLoS genetics | 2015 | PMID: 25647241 |
| Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. | Do R | Nature | 2015 | PMID: 25487149 |
| 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 |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/793a906e-889c-4bc4-8d0b-c59588d0f381 | - | - | - | - |
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Text-mined citations for rs730882090 ...
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Record last updated Oct 20, 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.