ClinVar Genomic variation as it relates to human health
NM_000527.4(LDLR):c.-138T>C
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000527.4(LDLR):c.-138T>C
Variation ID: 250952 Accession: VCV000250952.4
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11089411 (GRCh38) [ NCBI UCSC ] 19: 11200087 (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 Jan 6, 2024 Oct 28, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000527.4:c.-138T>C NM_001195798.1:c.-138T>C NM_001195799.1:c.-138T>C NM_001195800.1:c.-138T>C NM_001195803.1:c.-138T>C NR_163945.1:n.249A>G non-coding transcript variant NC_000019.10:g.11089411T>C NC_000019.9:g.11200087T>C NG_009060.1:g.5031T>C LRG_274:g.5031T>C LRG_274t1:c.-138T>C - Protein change
- Other names
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- Canonical SPDI
- NC_000019.10:11089410:T:C
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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.
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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 |
3998 | 4269 | |
LDLR-AS1 | - | - | - | GRCh38 | - | 202 |
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
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
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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 (3) |
reviewed by expert panel
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Oct 28, 2022 | RCV000237538.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 8, 2022 | RCV003477846.1 |
Submissions - Germline
Classification
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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
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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
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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
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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
(Oct 28, 2022)
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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
Accession: SCV002817162.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
The NM_000527.4(LDLR):c.-138T>C variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PS3_supporting) as defined by the ClinGen … (more)
The NM_000527.4(LDLR):c.-138T>C variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PS3_supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2_Met : This variant is absent from gnomAD (v.2.1.1). PS3_supporting Met: Level 3 Assay: Luciferase Assay + COS cells. The variant T-45C (Hobbs' numbering: -45T>C) is in the proximal Sp1 binding site in repeat 3 of the 42 bp region of the promoter required for steroldependent regulation of transcription. In 1995 Sun et al ( PMID: 8589690) reported that the variant reduced transcriptional activity to approximately 43% of normal in the presence, and 25% in the absence of sterols in the medium (repressing variant). (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: SCV000294389.2
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Number of individuals with the variant: 1
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Uncertain significance
(Mar 01, 2016)
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criteria provided, single submitter
Method: curation, literature only
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Familial hypercholesterolemia
Affected status: unknown, not applicable
Allele origin:
germline,
not applicable
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Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge
Accession: SCV000599301.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Observation 1: Observation 2:
Comment on evidence:
Assay Description:Heterologous cells (COS), luciferase assays
Result:
40-50% reporter gene expression
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Uncertain significance
(Sep 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004219948.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
This variant has not been described in online databases. It also has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, … (more)
This variant has not been described in online databases. It also has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in an affected individual with familial hypercholesterolemia (PMID: 8589690 (1995)). Functional studies found that this variant reduced promotor activity compared to wild type (PMIDs: 8589690 (1995), 25248394 (2015), 31395865 (2019)). Based on the available information, we are unable to determine the clinical significance of this variant. (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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Saturation mutagenesis of twenty disease-associated regulatory elements at single base-pair resolution. | Kircher M | Nature communications | 2019 | PMID: 31395865 |
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 |
RNAsnp: efficient detection of local RNA secondary structure changes induced by SNPs. | Sabarinathan R | Human mutation | 2013 | PMID: 23315997 |
A mutation (T-45C) in the promoter region of the low-density-lipoprotein (LDL)-receptor gene is associated with a mild clinical phenotype in a patient with heterozygous familial hypercholesterolaemia (FH). | Sun XM | Human molecular genetics | 1995 | PMID: 8589690 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/a7eeabdf-37f5-4de1-b494-d7efd05bf01f | - | - | - | - |
Text-mined citations for rs879254372 ...
HelpRecord last updated May 01, 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.