This missense variant (also known as p.Ser566Arg in the mature protein) replaces serine with arginine at codon 587 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 individuals affected with familial hypercholesterolemia (PMID: 16250003, 33740630) and in an individual affected with coronary artery disease (PMID: 27050191). It has also been reported in a healthy control individual (PMID: 30586733). This variant has been identified in 4/251490 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.
ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.1761C>G (p.Ser587Arg)
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.
(8)
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.
Uncertain significance
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000527.5(LDLR):c.1761C>G (p.Ser587Arg)
Variation ID: 252021 Accession: VCV000252021.12
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19p13.2 19: 11116914 (GRCh38) [ NCBI UCSC ] 19: 11227590 (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 Sep 16, 2024 Jan 4, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.1761C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Ser587Arg missense NM_001195798.2:c.1761C>G NP_001182727.1:p.Ser587Arg missense NM_001195799.2:c.1638C>G NP_001182728.1:p.Ser546Arg missense NM_001195800.2:c.1257C>G NP_001182729.1:p.Ser419Arg missense NM_001195803.2:c.1380C>G NP_001182732.1:p.Ser460Arg missense NC_000019.10:g.11116914C>G NC_000019.9:g.11227590C>G NG_009060.1:g.32534C>G LRG_274:g.32534C>G LRG_274t1:c.1761C>G LRG_274p1:p.Ser587Arg - Protein change
- S587R, S419R, S460R, S546R
- Other names
- -
- Canonical SPDI
- NC_000019.10:11116913:C:G
-
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.
-
Trans-Omics for Precision Medicine (TOPMed) 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 |
4075 | 4351 | |
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. |
|---|---|---|---|---|
| Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
|
Oct 6, 2023 | RCV000238260.6 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Jun 25, 2023 | RCV000775076.7 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Apr 13, 2022 | RCV002411089.2 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jan 4, 2024 | RCV004701341.1 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Mar 25, 2016)
|
criteria provided, single submitter
Method: literature only
|
Familial hypercholesterolemia
Affected status: yes
Allele origin:
germline
|
LDLR-LOVD, British Heart Foundation
Accession: SCV000295643.2
First in ClinVar: Jul 29, 2016 Last updated: May 30, 2018 |
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(May 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000909178.4
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant (also known as p.Ser566Arg in the mature protein) replaces serine with arginine at codon 587 of the LDLR protein. Computational prediction suggests … (more)
This missense variant (also known as p.Ser566Arg in the mature protein) replaces serine with arginine at codon 587 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 individuals affected with familial hypercholesterolemia (PMID: 16250003, 33740630) and in an individual affected with coronary artery disease (PMID: 27050191). It has also been reported in a healthy control individual (PMID: 30586733). This variant has been identified in 4/251490 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)
|
|
|
Uncertain significance
(Jun 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004397372.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant … (more)
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. ClinVar contains an entry for this variant (Variation ID: 252021). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 16250003, 20506408, 33740630). This variant is present in population databases (rs753430282, gnomAD 0.004%). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 587 of the LDLR protein (p.Ser587Arg). (less)
|
|
|
Uncertain Significance
(Oct 06, 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: SCV004822495.1
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 missense variant (also known as p.Ser566Arg in the mature protein) replaces serine with arginine at codon 587 of the LDLR protein. Computational prediction suggests … (more)
This missense variant (also known as p.Ser566Arg in the mature protein) replaces serine with arginine at codon 587 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 individuals affected with familial hypercholesterolemia (PMID: 16250003, 33740630) and in an individual affected with coronary artery disease (PMID: 27050191). It has also been reported in a healthy control individual (PMID: 30586733). This variant has been identified in 4/251490 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)
Number of individuals with the variant: 4
|
|
|
Uncertain significance
(Apr 13, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002716040.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.S587R variant (also known as c.1761C>G), located in coding exon 12 of the LDLR gene, results from a C to G substitution at nucleotide … (more)
The p.S587R variant (also known as c.1761C>G), located in coding exon 12 of the LDLR gene, results from a C to G substitution at nucleotide position 1761. The serine at codon 587 is replaced by arginine, an amino acid with dissimilar properties. This alteration was detected in a hypercholesterolemia, coronary artery cohorts; however, clinical details were limited (Fouchier SW et al. Hum. Mutat., 2005 Dec;26:550-6; Khera AV et al. J. Am. Coll. Cardiol., 2016 Jun;67:2578-89; Leren TP et al. Atherosclerosis, 2021 04;322:61-66). This alteration was also detected in a control subject in a whole exome sequencing cohort (Khera AV et al. Circulation, 2019 03;139:1593-1602). This amino acid position is well 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)
|
|
|
Uncertain significance
(Jan 04, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV005201892.1
First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
Comment:
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; … (more)
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; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 16250003, 20506408, 27050191, 30586733, 27044878, 37409534, 33740630) (less)
|
|
|
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: SCV000606507.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
|
|
|
not provided
(-)
|
no classification provided
Method: phenotyping only
|
Hypercholesterolemia, familial, 1
Hypercholesterolemia, familial, 1
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
maternal
|
GenomeConnect, ClinGen
Accession: SCV000607061.2
First in ClinVar: Jul 29, 2016 Last updated: Jun 17, 2024 |
Comment:
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical … (more)
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Failure to thrive (present) , Short stature (present) , Abnormality of movement (present) , Generalized hypotonia (present) , Abnormality of coordination (present) , Cognitive impairment … (more)
Failure to thrive (present) , Short stature (present) , Abnormality of movement (present) , Generalized hypotonia (present) , Abnormality of coordination (present) , Cognitive impairment (present) , Stereotypy (present) , Abnormality of the musculature of the limbs (present) , Abnormality of muscle physiology (present) , Abnormality of the large intestine (present) , Feeding difficulties (present) , Recurrent infections (present) (less)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: female
Method: Sanger Sequencing
Testing laboratory: Baylor Genetics
Date variant was reported to submitter: 2012-06-27
Testing laboratory interpretation: Uncertain significance
|
Comment:
Comment:
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. ClinVar contains an entry for this variant (Variation ID: 252021). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 16250003, 20506408, 33740630). This variant is present in population databases (rs753430282, gnomAD 0.004%). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 587 of the LDLR protein (p.Ser587Arg).
Comment:
This missense variant (also known as p.Ser566Arg in the mature protein) replaces serine with arginine at codon 587 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 individuals affected with familial hypercholesterolemia (PMID: 16250003, 33740630) and in an individual affected with coronary artery disease (PMID: 27050191). It has also been reported in a healthy control individual (PMID: 30586733). This variant has been identified in 4/251490 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.
Comment:
The p.S587R variant (also known as c.1761C>G), located in coding exon 12 of the LDLR gene, results from a C to G substitution at nucleotide position 1761. The serine at codon 587 is replaced by arginine, an amino acid with dissimilar properties. This alteration was detected in a hypercholesterolemia, coronary artery cohorts; however, clinical details were limited (Fouchier SW et al. Hum. Mutat., 2005 Dec;26:550-6; Khera AV et al. J. Am. Coll. Cardiol., 2016 Jun;67:2578-89; Leren TP et al. Atherosclerosis, 2021 04;322:61-66). This alteration was also detected in a control subject in a whole exome sequencing cohort (Khera AV et al. Circulation, 2019 03;139:1593-1602). This amino acid position is well 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:
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; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 16250003, 20506408, 27050191, 30586733, 27044878, 37409534, 33740630)
Comment:
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the 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:
This missense variant (also known as p.Ser566Arg in the mature protein) replaces serine with arginine at codon 587 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 individuals affected with familial hypercholesterolemia (PMID: 16250003, 33740630) and in an individual affected with coronary artery disease (PMID: 27050191). It has also been reported in a healthy control individual (PMID: 30586733). This variant has been identified in 4/251490 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.
Comment:
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. ClinVar contains an entry for this variant (Variation ID: 252021). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 16250003, 20506408, 33740630). This variant is present in population databases (rs753430282, gnomAD 0.004%). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 587 of the LDLR protein (p.Ser587Arg).
Comment:
This missense variant (also known as p.Ser566Arg in the mature protein) replaces serine with arginine at codon 587 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 individuals affected with familial hypercholesterolemia (PMID: 16250003, 33740630) and in an individual affected with coronary artery disease (PMID: 27050191). It has also been reported in a healthy control individual (PMID: 30586733). This variant has been identified in 4/251490 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.
Comment:
The p.S587R variant (also known as c.1761C>G), located in coding exon 12 of the LDLR gene, results from a C to G substitution at nucleotide position 1761. The serine at codon 587 is replaced by arginine, an amino acid with dissimilar properties. This alteration was detected in a hypercholesterolemia, coronary artery cohorts; however, clinical details were limited (Fouchier SW et al. Hum. Mutat., 2005 Dec;26:550-6; Khera AV et al. J. Am. Coll. Cardiol., 2016 Jun;67:2578-89; Leren TP et al. Atherosclerosis, 2021 04;322:61-66). This alteration was also detected in a control subject in a whole exome sequencing cohort (Khera AV et al. Circulation, 2019 03;139:1593-1602). This amino acid position is well 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:
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; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 16250003, 20506408, 27050191, 30586733, 27044878, 37409534, 33740630)
Comment:
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| Mutation type classification and pathogenicity assignment of sixteen missense variants located in the EGF-precursor homology domain of the LDLR. | Galicia-Garcia U | Scientific reports | 2020 | PMID: 32015373 |
| Whole-Genome Sequencing to Characterize Monogenic and Polygenic Contributions in Patients Hospitalized With Early-Onset Myocardial Infarction. | Khera AV | Circulation | 2019 | PMID: 30586733 |
| Diagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia. | Khera AV | Journal of the American College of Cardiology | 2016 | PMID: 27050191 |
| Functionality of sequence variants in the genes coding for the low-density lipoprotein receptor and apolipoprotein B in individuals with inherited hypercholesterolemia. | Huijgen R | Human mutation | 2010 | PMID: 20506408 |
| Update of the molecular basis of familial hypercholesterolemia in The Netherlands. | Fouchier SW | Human mutation | 2005 | PMID: 16250003 |
Text-mined citations for rs753430282 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.