ClinVar Genomic variation as it relates to human health
NC_000019.10:g.11089429C>T
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NC_000019.10:g.11089429C>T
Variation ID: 226299 Accession: VCV000226299.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11089429 (GRCh38) [ NCBI UCSC ] 19: 11200105 (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 May 22, 2016 May 1, 2024 Apr 28, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000527.4:c.-120C>T NM_001195798.1:c.-120C>T NM_001195799.1:c.-120C>T NM_001195800.1:c.-120C>T NM_001195803.1:c.-120C>T NR_163945.1:n.231G>A non-coding transcript variant NC_000019.10:g.11089429C>T NC_000019.9:g.11200105C>T NG_009060.1:g.5049C>T LRG_274:g.5049C>T LRG_274t1:c.-120C>T - Protein change
- Other names
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- Canonical SPDI
- NC_000019.10:11089428: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
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
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
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. |
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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
Help
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 (7) |
reviewed by expert panel
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Apr 28, 2023 | RCV000211703.21 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Apr 27, 2023 | RCV001190436.14 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 31, 2020 | RCV002354590.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 19, 2023 | RCV003223624.8 |
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
(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: SCV004022378.1 First in ClinVar: Aug 05, 2023 Last updated: Aug 05, 2023 |
Comment:
The NM_000527.4(LDLR):c.-120C>T variant is classified as Uncertain significance - conflicting evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PP1, PP4, PS3_Supporting, PS4_Supporting and BP2 … (more)
The NM_000527.4(LDLR):c.-120C>T variant is classified as Uncertain significance - conflicting evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PP1, PP4, PS3_Supporting, PS4_Supporting and BP2 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 - PopMax MAF = 0.00001470 (0.001470%) in European non-Finnish (gnomAD v3.2.1). It is below 0.02%, so met. PP1 - Variant segregates with the FH phenotype in: - 2 relatives from 1 family from Francová et al. 2004 (PMID: 15303010): 2 relatives with the phenotype (LDL cholesterol concentration between 93 and 99.5 percentile for age and sex) have the variant; - 1 relative from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA): 1 relative without the phenotype and without the variant. 3 segregations, so PP1 is met. PS3_supporting - Level 3 FS: Francová et al. 2004 (PMID: 15303010) : Heterologous cells (HepG2), luciferase assays - results: 3% reporter gene transcription (Reported as c.-27C>T in the paper). --- it is below 50%, so PS3_Supporting is met. PS4_supporting - variant meets PM2 and was identified in: - 1 index case with Simon Broome possible from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), France; - 1 index case with Simon Broome possible from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), Czech Republic; - 1 index case with Dutch lipid clinic network >=6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA), Australia. 3 cases, so PS4_Supporting is met PP4 - variant meets PM2 and was identified in 3 unrelated index cases who fulfill clinical FH criteria from different labs (please see PS4 for details), so PP4 is met. BP2 - Variant identified in 1 index case and 1 relative, both carriers of NM_000527.4(LDLR):c.2416dupG (p.Val806Glyfs*11) in trans with LDLc values of 4.3 mmol/l (16y) and 5.9 mmol/l (11y), respectively. 2nd variant is classified as Pathogenic by these guidelines and phenotype is clearly of heterozygous FH, so BP2 is met. (less)
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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: SCV000294395.2
First in ClinVar: Jul 29, 2016 Last updated: Sep 30, 2017 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 1
Observation 3:
Number of individuals with the variant: 1
Observation 4:
Number of individuals with the variant: 1
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Likely benign
(Mar 27, 2017)
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criteria provided, single submitter
Method: clinical testing, in vitro
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Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
inherited,
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: SCV000540711.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Comment:
A functional analysis was previously published (Francova et al, 2004). Only 3% of activity in comparing with wt promoter.
Observation 1:
Number of individuals with the variant: 2
Clinical Features:
Hypercholesterolemia (present)
Age: 16-54 years
Sex: mixed
Ethnicity/Population group: Caucasian
Geographic origin: Czech Republic, Europe
Tissue: Whole blood
Method: ADH Master kit (Multiplicom)
Observation 2:
Sex: male
Comment on evidence:
A functional analysis has been previously published (Francova et al, 2004). Only 3% of activity in comparing with wt promoter.
Method: Measurement of firefly and renilla luciferase activities using Dual-Luciferase reporter assay systém (Promega)
Result:
3% activity of promoter.
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Likely pathogenic
(Mar 01, 2016)
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criteria provided, single submitter
Method: research
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Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Fundacion Hipercolesterolemia Familiar
Study: SAFEHEART
Accession: SCV000607395.1 First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
Observation 1: Observation 2:
Comment on evidence:
Heterologous cells (HepG2), luciferase assays
Result:
3% reporter gene transcription
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Uncertain significance
(Apr 27, 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: SCV001357925.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant (also known as -27C>T , counting from the transcription start site) changes a conserved nucleotide in the promoter region of the LDLR gene. … (more)
This variant (also known as -27C>T , counting from the transcription start site) changes a conserved nucleotide in the promoter region of the LDLR gene. An experimental functional study has shown that this variant abolishes the promoter activity in a luciferase-based assay performed in HepG2 cells (PMID: 15303010). However, this variant has shown no significant impact on the promoter activity in a similar luciferase-based assay performed in Huh7 cells (PMID: 25248394), as well as in a similar assay performed in HEK293 cells (PMID: 31395865). This variant has been reported in an individual affected with familial hypercholesterolemia (PMID: 30293936) and in 3 related individuals affected with familial hypercholesterolemia (PMID: 15303010). This variant has also been reported in a 70-year old individual with very low Dutch Lipid Clinical Network-score (PMID: 29974534). This variant has been identified in 1/31400 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to the conflicting functional study results and insufficient clinical evidence, the role of this variant in disease cannot be determined conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Sep 03, 2022)
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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: SCV003268571.1
First in ClinVar: Feb 07, 2023 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. This … (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. This variant is present in population databases (no rsID available, gnomAD 0.03%). This variant has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 15303010, 21538688). ClinVar contains an entry for this variant (Variation ID: 226299). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects LDLR function (PMID: 15303010). 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
(Apr 19, 2023)
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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: SCV003919454.1
First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Functional studies are conflicting as to whether this variant significantly alters promoter activity (Francova et … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Functional studies are conflicting as to whether this variant significantly alters promoter activity (Francova et al., 2004; Khamis et al., 2015; Kircher et al., 2019); Also known as -27C>T; This variant is associated with the following publications: (PMID: 31395865, 21310417, 22698793, 29974534, 15303010, 21538688, 34456049, 30293936, 25248394, 35047021) (less)
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Uncertain Significance
(Feb 05, 2024)
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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: SCV004830632.1
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 (also known as -27C>T , counting from the transcription start site) changes a conserved nucleotide in the promoter region of the LDLR gene. … (more)
This variant (also known as -27C>T , counting from the transcription start site) changes a conserved nucleotide in the promoter region of the LDLR gene. An experimental functional study has shown that this variant abolishes the promoter activity in a luciferase-based assay performed in HepG2 cells (PMID: 15303010). However, this variant has shown no significant impact on the promoter activity in a similar luciferase-based assay performed in Huh7 cells (PMID: 25248394), as well as in a similar assay performed in HEK293 cells (PMID: 31395865). This variant has been reported in an individual affected with familial hypercholesterolemia (PMID: 30293936) and in 3 related individuals affected with familial hypercholesterolemia (PMID: 15303010). This variant has also been reported in a 70-year old individual with very low Dutch Lipid Clinical Network-score (PMID: 29974534). This variant has been identified in 1/31400 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to the conflicting functional study results and insufficient clinical evidence, the role of this variant in disease cannot be determined conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 5
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Uncertain significance
(Mar 31, 2020)
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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: SCV002649777.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.-120C>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.-120C>T variant is located in the 5' untranslated region (5’ UTR) of the LDLR gene. This variant results from a C to T substitution 120 bases upstream from the first translated codon. This alteration has been reported to segregate with disease in one small family with familial hypercholesterolemia (FH) (Francová H et al. J. Inherit. Metab. Dis., 2004;27:523-8; described as c.-27C>T). This variant has also been reported in an FH genetic testing cohort, but clinical details were limited (Martín-Campos JM et al. J Clin Lipidol Oct;12:1452-1462). Functional studies performed in vitro suggest that this variant may reduce LDLR transcription levels, but while one study suggested that this alteration reduced transcription to background levels, two other studies suggest that the variant reduces transcription by only 10-17%, and the clinical relevance of that degree of reduction is unclear (Francová H et al. J. Inherit. Metab. Dis., 2004;27:523-8; Khamis A et al. Eur. J. Hum. Genet., 2015 Jun;23:790-5; Kircher M et al. Nat Commun, 2019 08;10:3583). This nucleotide position is highly conserved in available vertebrate species. Since supporting evidence is limited and conflicting at this time, the clinical significance of this alteration remains unclear. (less)
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Pathogenic
(Apr 17, 2015)
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no assertion criteria provided
Method: clinical testing
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Familial hypercholesterolemia
Affected status: yes
Allele origin:
germline
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Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital
Accession: SCV000268529.1
First in ClinVar: May 22, 2016 Last updated: May 22, 2016 |
Number of individuals with the variant: 1
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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: SCV000605987.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
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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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Saturation mutagenesis of twenty disease-associated regulatory elements at single base-pair resolution. | Kircher M | Nature communications | 2019 | PMID: 31395865 |
Autosomal dominant hypercholesterolemia in Catalonia: Correspondence between clinical-biochemical and genetic diagnostics in 967 patients studied in a multicenter clinical setting. | Martín-Campos JM | Journal of clinical lipidology | 2018 | PMID: 30293936 |
Genetic testing for familial hypercholesterolemia among survivors of acute coronary syndrome. | Benedek P | Journal of internal medicine | 2018 | PMID: 29974534 |
Functional analysis of four LDLR 5'UTR and promoter variants in patients with familial hypercholesterolaemia. | Khamis A | European journal of human genetics : EJHG | 2015 | PMID: 25248394 |
The molecular basis of familial hypercholesterolemia in the Czech Republic: spectrum of LDLR mutations and genotype-phenotype correlations. | Tichý L | Atherosclerosis | 2012 | PMID: 22698793 |
Functional analysis of LDLR promoter and 5' UTR mutations in subjects with clinical diagnosis of familial hypercholesterolemia. | De Castro-Orós I | Human mutation | 2011 | PMID: 21538688 |
Genetic diagnosis of familial hypercholesterolemia using a DNA-array based platform. | Alonso R | Clinical biochemistry | 2009 | PMID: 19318025 |
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 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/fd6734d6-53a4-4f4f-8126-edf0993e4c4f | - | - | - | - |
Text-mined citations for rs875989886 ...
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.