ClinVar Genomic variation as it relates to human health
NC_000019.10:g.11089396C>T
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Likely pathogenic(1); Uncertain significance(7)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NC_000019.10:g.11089396C>T
Variation ID: 250944 Accession: VCV000250944.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11089396 (GRCh38) [ NCBI UCSC ] 19: 11200072 (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 Jul 29, 2016 Sep 16, 2024 Jul 17, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000527.4:c.-153C>T NM_001195798.1:c.-153C>T NM_001195799.1:c.-153C>T NM_001195800.1:c.-153C>T NM_001195803.1:c.-153C>T NR_163945.1:n.264G>A non-coding transcript variant NC_000019.10:g.11089396C>T NC_000019.9:g.11200072C>T NG_009060.1:g.5016C>T LRG_274:g.5016C>T LRG_274t1:c.-153C>T - Protein change
- Other names
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- Canonical SPDI
- NC_000019.10:11089395:C:T
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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.
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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 | ||
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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
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. |
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LDLR | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
4070 | 4346 | |
LDLR-AS1 | - | - | - | GRCh38 | - | 204 |
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
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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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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Dec 13, 2023 | RCV000238251.14 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jun 15, 2023 | RCV000775251.18 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jul 17, 2024 | RCV001508836.18 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 13, 2023 | RCV004020944.1 |
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
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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. |
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Uncertain significance
(Mar 25, 2016)
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criteria provided, single submitter
Method: literature only
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Familial hypercholesterolemia
Affected status: yes
Allele origin:
germline
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LDLR-LOVD, British Heart Foundation
Accession: SCV000294379.2
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Number of individuals with the variant: 1
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Likely pathogenic
(Nov 05, 2016)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation
Additional submitter:
Centre of Molecular Biology and Gene Therapy, University Hospital Brno
Accession: SCV000540708.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Comment:
Disrupt Sterol Regulatory Element sequence.
Number of individuals with the variant: 1
Clinical Features:
Hypercholesterolemia (present)
Family history: yes
Age: 50-59 years
Sex: female
Ethnicity/Population group: Caucasian
Geographic origin: Czech Republic
Tissue: Whole blood
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Uncertain significance
(Jun 15, 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: SCV000909510.4
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This variant is located in the conserved sterol-dependent regulatory element 2 (SRE2) in the promoter region of the LDLR gene. This variant is also known … (more)
This variant is located in the conserved sterol-dependent regulatory element 2 (SRE2) in the promoter region of the LDLR gene. This variant is also known as -60C>T based on the position calculated from the transcription start site (PMID: 15303010). An experimental luciferase-based functional assay has suggested that this variant may reduce LDLR promoter activity significantly, but actual data were not shown (PMID: 15303010). Another experimental functional study using high-throughput screening has shown that this variant causes an approximately 40% repression in promoter activity (PMID: 31395865). To our knowledge, it has not been shown whether this variant results in reduced LDLR expression and function in individuals carrying this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 15303010, 35052492; Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, 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)
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Uncertain significance
(Aug 03, 2019)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001715231.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Number of individuals with the variant: 1
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Uncertain significance
(Aug 12, 2021)
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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: SCV002312518.2
First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023 |
Comment:
This variant occurs in a non-coding region of the LDLR gene. It does not change the encoded amino acid sequence of the LDLR protein. The … (more)
This variant occurs in a non-coding region of the LDLR gene. It does not change the encoded amino acid sequence of the LDLR protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has been observed in individual(s) with familial hypercholesterolemia (PMID: 15303010). This variant is also known as c.-60C>T. ClinVar contains an entry for this variant (Variation ID: 250944). Studies have shown that this variant alters LDLR gene expression (PMID: 31395865). 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. (less)
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Uncertain Significance
(Dec 13, 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: SCV004833335.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This variant is located in the conserved sterol-dependent regulatory element 2 (SRE2) in the promoter region of the LDLR gene. This variant is also known … (more)
This variant is located in the conserved sterol-dependent regulatory element 2 (SRE2) in the promoter region of the LDLR gene. This variant is also known as -60C>T based on the position calculated from the transcription start site (PMID: 15303010). An experimental luciferase-based functional assay has suggested that this variant may reduce LDLR promoter activity significantly, but actual data were not shown (PMID: 15303010). Another experimental functional study using high-throughput screening has shown that this variant causes an approximately 40% repression in promoter activity (PMID: 31395865). To our knowledge, it has not been shown whether this variant results in reduced LDLR expression and function in individuals carrying this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 15303010, 35052492; Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, 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: 3
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Uncertain significance
(Oct 13, 2023)
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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: SCV005036037.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
The c.-153C>T variant is located in the 5' untranslated region (5’ UTR) of the LDLR gene. This variant results from a C to T substitution … (more)
The c.-153C>T variant is located in the 5' untranslated region (5’ UTR) of the LDLR gene. This variant results from a C to T substitution 153 bases upstream from the first translated codon. This variant (also referred to as -60C>T) has been detected in individuals with hypercholesterolemia; however, reported cases may overlap (Francová H et al. J Inherit Metab Dis. 2004 ;27(4):523-8; Dušková L et al. Atherosclerosis, 2011 May;216:139-45; Ambry internal data). Functional studies have suggested that this variant may reduce promoter activity; however, experimental data was not provided by one study (Francová H et al. J Inherit Metab Dis. 2004 ;27(4):523-8; Kircher M et al. Nat Commun, 2019 Aug;10:3583). This nucleotide position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Jul 17, 2024)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001871090.2
First in ClinVar: Sep 19, 2021 Last updated: Sep 16, 2024 |
Comment:
Published functional studies suggest a damaging effect through impaired promoter activity (PMID: 31395865); Reliable data are not available in large population cohorts to assess the … (more)
Published functional studies suggest a damaging effect through impaired promoter activity (PMID: 31395865); Reliable data are not available in large population cohorts to assess the frequency of this variant in publicly available databases; however, this variant has not been detected at significant frequency in presumably healthy individuals tested at GeneDx.; Also known as c.-60C>T; This variant is associated with the following publications: (PMID: 17625505, 23315997, 15303010, 21310417, 22698793, 35052492, 38955586, 31395865) (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Establishing the Mutational Spectrum of Hungarian Patients with Familial Hypercholesterolemia. | Madar L | Genes | 2022 | PMID: 35052492 |
A catalog of the pathogenic mutations of LDL receptor gene in Japanese familial hypercholesterolemia. | Tada H | Journal of clinical lipidology | 2020 | PMID: 32331935 |
Saturation mutagenesis of twenty disease-associated regulatory elements at single base-pair resolution. | Kircher M | Nature communications | 2019 | PMID: 31395865 |
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 |
New promoter mutations in the low-density lipoprotein receptor gene which induce familial hypercholesterolaemia phenotype: molecular and functional analysis. | Francová H | Journal of inherited metabolic disease | 2004 | PMID: 15303010 |
Text-mined citations for rs879254366 ...
HelpRecord last updated Oct 08, 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.