ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.859G>A (p.Gly287Ser)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000527.5(LDLR):c.859G>A (p.Gly287Ser)
Variation ID: 161280 Accession: VCV000161280.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11107433 (GRCh38) [ NCBI UCSC ] 19: 11218109 (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 Dec 7, 2014 May 1, 2024 Apr 28, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000527.5:c.859G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Gly287Ser missense NM_001195798.2:c.859G>A NP_001182727.1:p.Gly287Ser missense NM_001195799.2:c.736G>A NP_001182728.1:p.Gly246Ser missense NM_001195800.2:c.355G>A NP_001182729.1:p.Gly119Ser missense NM_001195803.2:c.478G>A NP_001182732.1:p.Gly160Ser missense NC_000019.10:g.11107433G>A NC_000019.9:g.11218109G>A NG_009060.1:g.23053G>A LRG_274:g.23053G>A LRG_274t1:c.859G>A LRG_274p1:p.Gly287Ser - Protein change
- G287S, G160S, G246S, G119S
- Other names
- NM_000527.5(LDLR):c.859G>A
- p.Gly287Ser
- Canonical SPDI
- NC_000019.10:11107432: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.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
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 |
4070 | 4346 |
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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Uncertain significance (5) |
reviewed by expert panel
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Apr 28, 2023 | RCV000237748.16 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Oct 22, 2023 | RCV001176040.15 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 26, 2022 | RCV002444606.9 | |
Uncertain significance (1) |
no assertion criteria provided
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Jun 1, 2014 | RCV002051673.10 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 10, 2022 | RCV002307407.8 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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
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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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Uncertain significance
(Apr 28, 2023)
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reviewed by expert panel
Method: curation
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Hypercholesterolemia, familial, 1
(Semidominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV004022420.1 First in ClinVar: Aug 05, 2023 Last updated: Aug 05, 2023 |
Comment:
The NM_000527.5 (LDLR):c.859G>A (p.Gly287Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PM5) as defined … (more)
The NM_000527.5 (LDLR):c.859G>A (p.Gly287Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PM5) 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: PM2: PopMaxMAF=0.00003 in South Asian population in gnomAD (gnomAD v2.1.1). PP3: REVEL=0.902. PM5: One other variant at same codon: NM_000527.5 (LDLR):c.859G>T (p.Gly287Cys), ClinVarID 251489, is classified as Pathogenic by these guidelines, therefore PM5 is met. PS3 not met: Functional data is not available. (less)
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Uncertain Significance
(Dec 01, 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: SCV004820225.1
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:
Variant of Uncertain Significance due to insufficient evidence: This missense variant (also known as p.Gly266Ser in the mature protein) is located in the LDLR type … (more)
Variant of Uncertain Significance due to insufficient evidence: This missense variant (also known as p.Gly266Ser in the mature protein) is located in the LDLR type A repeat 7 of the ligand binding domain of the LDLR protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been identified in an individual affected with familial hypercholesterolemia (PMID: 23669246). This variant has also been identified in 3/246246 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. (less)
Number of individuals with the variant: 7
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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: SCV000295014.2
First in ClinVar: Jul 29, 2016 Last updated: May 30, 2018 |
Number of individuals with the variant: 1
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Likely pathogenic
(May 18, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV001653469.1
First in ClinVar: Jun 03, 2021 Last updated: Jun 03, 2021 |
Sex: mixed
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Uncertain significance
(Oct 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002600399.1
First in ClinVar: Nov 19, 2022 Last updated: Nov 19, 2022 |
Comment:
Variant summary: LDLR c.859G>A (p.Gly287Ser) 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.859G>A (p.Gly287Ser) 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 8e-06 in 251434 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.859G>A has been reported in the literature in individuals affected with Hypercholesterolemia without strong evidence for causality (Futema_2013, Trinder_2020, Leren_2021). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Another variant located at the same amino acid has been reported in association with Hypercholesterolaemia in HGMD (p.G287C). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Mar 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV001339857.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant (also known as p.Gly266Ser in the mature protein) replaces glycine with serine at codon 287 of the LDLR protein. Computational prediction suggests … (more)
This missense variant (also known as p.Gly266Ser in the mature protein) replaces glycine with serine at codon 287 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with familial hypercholesterolemia (PMID: 23669246). This variant has been identified in 3/282818 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Likely pathogenic
(Oct 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003260467.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 287 of the LDLR protein (p.Gly287Ser). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 287 of the LDLR protein (p.Gly287Ser). This variant is present in population databases (rs375495026, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (PMID: 23669246, 33740630). ClinVar contains an entry for this variant (Variation ID: 161280). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. This variant disrupts the p.Gly287 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12730724, 17196209; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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Uncertain significance
(Oct 26, 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: SCV002679931.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.G287S variant (also known as c.859G>A), located in coding exon 6 of the LDLR gene, results from a G to A substitution at nucleotide … (more)
The p.G287S variant (also known as c.859G>A), located in coding exon 6 of the LDLR gene, results from a G to A substitution at nucleotide position 859. The glycine at codon 287 is replaced by serine, an amino acid with similar properties. This alteration has been reported in familial cholesterolemia (FH) cohorts; however, clinical details were limited (Futema M et al. Atherosclerosis, 2013 Jul;229:161-8; Leren TP et al. Atherosclerosis, 2021 04;322:61-66). Additionally, this alteration was reported in a control population of an early onset myocardial infarction cohort (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)
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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: SCV000606251.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
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Uncertain significance
(Jun 01, 2014)
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no assertion criteria provided
Method: research
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Hypercholesterolaemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190301.1 First in ClinVar: Dec 07, 2014 Last updated: Dec 07, 2014
Comment:
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
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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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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 |
Polygenic Contribution to Low-Density Lipoprotein Cholesterol Levels and Cardiovascular Risk in Monogenic Familial Hypercholesterolemia. | Trinder M | Circulation. Genomic and precision medicine | 2020 | PMID: 33079599 |
Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. | Do R | Nature | 2015 | PMID: 25487149 |
Analysis of the frequency and spectrum of mutations recognised to cause familial hypercholesterolaemia in routine clinical practice in a UK specialist hospital lipid clinic. | Futema M | Atherosclerosis | 2013 | PMID: 23669246 |
Detection of familial hypercholesterolemia in a cohort of children with hypercholesterolemia: results of a family and DNA-based screening. | Campagna F | Atherosclerosis | 2008 | PMID: 17196209 |
Familial hypercholesterolemia in Morocco: first report of mutations in the LDL receptor gene. | El Messal M | Journal of human genetics | 2003 | PMID: 12730724 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/d76af77c-2e61-4be5-9121-173c148bc3db | - | - | - | - |
Text-mined citations for rs375495026 ...
HelpRecord last updated Oct 13, 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.