ClinVar Genomic variation as it relates to human health
NM_000527.4(LDLR):c.-156C>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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000527.4(LDLR):c.-156C>T
Variation ID: 250942 Accession: VCV000250942.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11089393 (GRCh38) [ NCBI UCSC ] 19: 11200069 (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 May 1, 2024 Mar 20, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000527.4:c.-156C>T NM_001195798.1:c.-156C>T NM_001195799.1:c.-156C>T NM_001195800.1:c.-156C>T NM_001195803.1:c.-156C>T NR_163945.1:n.267G>A non-coding transcript variant NC_000019.10:g.11089393C>T NC_000019.9:g.11200069C>T NG_009060.1:g.5013C>T LRG_274:g.5013C>T LRG_274t1:c.-156C>T - Protein change
- Other names
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- Canonical SPDI
- NC_000019.10:11089392: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.
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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
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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 (3) |
reviewed by expert panel
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Mar 20, 2023 | RCV000237296.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 21, 2022 | RCV000813804.15 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 14, 2019 | RCV002401928.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 1, 2022 | RCV003417847.4 |
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
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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
(Mar 20, 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
Accession: SCV004022391.1
First in ClinVar: Aug 05, 2023 Last updated: Aug 05, 2023 |
Comment:
The NM_000527.4(LDLR):c.-156C>T variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PS3_supporting, PS4_supporting, PP4) as defined by … (more)
The NM_000527.4(LDLR):c.-156C>T variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PS3_supporting, PS4_supporting, PP4) 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 - This variant is absent from gnomAD (gnomAD v2.1.1). PS3_supporting - Level 3 assay: PMID 31395865: Heterologous cells, luciferase assays - result - luciferase activity 15-17% of wild-type (repressing variant). ---- functional study is consistent with damaging effect. PS4_supporting - Variant meets PM2 and is identified in 2 index cases with definite FH: 1 index case with CT=439, LDL=377, severe CAD and Achilles tendon xanthomata from Germany (PMID: 14974088), and 1 index case with LDL >13 mmol/L, pCHD and tendon xanthomas from Italy (PMID: 31947532). PP4 - Variant meets PM2 and is identified in 2 index cases with definite FH (see PS4 for details), after alternative causes for high cholesterol were excluded. (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: SCV000294377.2
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 21, 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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Invitae
Accession: SCV000954180.5
First in ClinVar: Aug 14, 2019 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 not present in population databases (gnomAD no frequency). This variant has been observed in individuals with hypercholesterolemia (PMID: 14974088, 21382890, 28104544, 32977124, 33740630). ClinVar contains an entry for this variant (Variation ID: 250942). 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 01, 2022)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004137803.4
First in ClinVar: Nov 20, 2023 Last updated: Apr 15, 2024 |
Comment:
LDLR: PM1, PM2
Number of individuals with the variant: 1
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Uncertain Significance
(Nov 20, 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: SCV004840242.1
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 SREBP binding site in the promoter region of the LDLR gene. An experimental functional study measuring luciferase activity in … (more)
This variant is located in the SREBP binding site in the promoter region of the LDLR gene. An experimental functional study measuring luciferase activity in transfected HepG2 cells has shown that this variant causes a significant decrease in LDLR gene expression (PMID: 31395865). This variant has been reported in four heterozygous individuals affected with familial hypercholesterolemia (PMID: 14974088, 21382890, 28104544, 33740630). This variant has also been observed in homozygous state in one individual affected with severe homozygous familial hypercholesterolemia (PMID: 31947532, 32977124). It has been shown that this variant segregates with disease in two affected individuals in one family (PMID: 14974088). This variant has not been identified 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: 1
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Likely pathogenic
(Jan 14, 2019)
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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: SCV002708449.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.-156C>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.-156C>T variant is located in the 5' untranslated region (5’ UTR) of the LDLR gene. This variant results from a C to T substitution 156 nucleotides upstream from the first translated codon, and is located in the sterol regulatory element (SRE-1). This variant was reported to occur in the homozygous state in a 44 year-old individual with severe coronary artery disease, LDL-C of 377mg/dL, Achilles tendon xanthoma, periorbital xanthelasma, and sudden death who also had a family history of heart attack, sudden death, and hypercholesterolemia. A reportedly less severely affected sibling was heterozygous for the variant (Dedoussis GV et al. Hum. Mutat., 2004 Mar;23:285-6). In another study, this variant was detected in an individual from a familial hypercholesterolemia cohort, with LDL-C of 6.72mmol/L (Durst R et al. Atherosclerosis, 2017 02;257:55-63). Another alteration at this nucleotide position (c.156C>A) has been shown to impact transcriptional regulation of LDLR expression (Smith JR et al. J. Biol. Chem. 1990;265(4):2306-10; Wang X et al. J. Biol. Chem. 1993;268(19):14497-504). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (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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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 |
Homozygous familial hypercholesterolemia in Italy: Clinical and molecular features. | Bertolini S | Atherosclerosis | 2020 | PMID: 32977124 |
A Real-World Experience of Clinical, Biochemical and Genetic Assessment of Patients with Homozygous Familial Hypercholesterolemia. | Di Taranto MD | Journal of clinical medicine | 2020 | PMID: 31947532 |
Saturation mutagenesis of twenty disease-associated regulatory elements at single base-pair resolution. | Kircher M | Nature communications | 2019 | PMID: 31395865 |
Molecular genetics of familial hypercholesterolemia in Israel-revisited. | Durst R | Atherosclerosis | 2017 | PMID: 28104544 |
Molecular basis of autosomal dominant hypercholesterolemia: assessment in a large cohort of hypercholesterolemic children. | van der Graaf A | Circulation | 2011 | PMID: 21382890 |
Molecular characterization of familial hypercholesterolemia in German and Greek patients. | Dedoussis GV | Human mutation | 2004 | PMID: 14974088 |
Nuclear protein that binds sterol regulatory element of low density lipoprotein receptor promoter. II. Purification and characterization. | Wang X | The Journal of biological chemistry | 1993 | PMID: 8314806 |
Identification of nucleotides responsible for enhancer activity of sterol regulatory element in low density lipoprotein receptor gene. | Smith JR | The Journal of biological chemistry | 1990 | PMID: 2298751 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/b26cdb00-be2b-49b3-b720-85d27e07d351 | - | - | - | - |
Text-mined citations for rs879254364 ...
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.