ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.2390-2A>G
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_000527.5(LDLR):c.2390-2A>G
Variation ID: 252313 Accession: VCV000252313.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11129511 (GRCh38) [ NCBI UCSC ] 19: 11240187 (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 Sep 30, 2017 May 1, 2024 Jul 26, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000527.5:c.2390-2A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NM_001195798.2:c.2390-2A>G splice acceptor NM_001195799.2:c.2267-2A>G splice acceptor NM_001195800.2:c.1886-2A>G splice acceptor NM_001195803.2:c.1856-2A>G splice acceptor NC_000019.10:g.11129511A>G NC_000019.9:g.11240187A>G NG_009060.1:g.45131A>G LRG_274:g.45131A>G LRG_274t1:c.2390-2A>G - Protein change
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- Other names
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- Canonical SPDI
- NC_000019.10:11129510:A:G
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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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The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 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 | ||
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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 |
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
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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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Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jun 5, 2019 | RCV000238115.4 | |
Pathogenic (2) |
criteria provided, single submitter
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Jun 4, 2023 | RCV001828123.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 26, 2023 | RCV002450749.2 |
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
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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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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: SCV000295983.2
First in ClinVar: Jul 29, 2016 Last updated: May 26, 2018 |
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
Observation 5:
Number of individuals with the variant: 1
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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: SCV000607701.1 First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
Observation 1:
Comment on evidence:
%MAF(ExAC):0.000825
Observation 2:
Comment on evidence:
Hmz patients' fibroblasts, RNA and 125I-LDL assays
Result:
retention of 62 nts from intron 16 (p.Val797Glyfs*153); ~50% LDL-LDLR binding, <2% LDL-LDLR interlization and degradation
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Pathogenic
(Jun 04, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000544639.6
First in ClinVar: Jul 29, 2016 Last updated: Feb 28, 2024 |
Comment:
This variant is present in population databases (rs767790696, gnomAD 0.0009%). This sequence change affects an acceptor splice site in intron 16 of the LDLR gene. … (more)
This variant is present in population databases (rs767790696, gnomAD 0.0009%). This sequence change affects an acceptor splice site in intron 16 of the LDLR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). Disruption of this splice site has been observed in individuals with familial hypercholesterolemia (PMID: 8141835, 10441197, 12052488, 16465405, 20145306, 21382890, 22698793). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site is associated with altered splicing resulting in unknown protein product impact (PMID: 8141835). ClinVar contains an entry for this variant (Variation ID: 252313). (less)
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Pathogenic
(Jan 02, 2018)
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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:
germline
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Robarts Research Institute, Western University
Accession: SCV000782940.1
First in ClinVar: May 26, 2018 Last updated: May 26, 2018 |
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Pathogenic
(Jun 05, 2019)
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criteria provided, single submitter
Method: research
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Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
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Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia
Accession: SCV001432636.1
First in ClinVar: Sep 19, 2020 Last updated: Sep 19, 2020 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Dutch Lipid Clinic Network Criteria score (present) , low-density lipoprotein cholesterol level (present)
Observation 3:
Number of individuals with the variant: 1
Clinical Features:
Dutch Lipid Clinic Network Criteria score (present) , low-density lipoprotein cholesterol level (present)
Observation 4:
Number of individuals with the variant: 1
Clinical Features:
Dutch Lipid Clinic Network Criteria score (present) , low-density lipoprotein cholesterol level (present)
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Pathogenic
(Jul 26, 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: SCV002737105.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.2390-2A>G intronic variant results from an A to G substitution two nucleotides before coding exon 17 of the LDLR gene. Alterations that disrupt the … (more)
The c.2390-2A>G intronic variant results from an A to G substitution two nucleotides before coding exon 17 of the LDLR gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from gnomAD, the G allele has an overall frequency of <0.001% (1/251074) total alleles studied. The highest observed frequency was 0.001% (1/113722) of European (non-Finnish) alleles. This alteration has been reported in multiple familial hypercholesterolemia (FH) cohorts and functional studies have shown this alteration to have an impact on splicing (Lombardi, 1993; Peeters, 1999; Lind, 2002; Alonso, 2009; Chmara, 2010; van der Graaf, 2011; Huijgen, 2012). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Based on the available evidence, this alteration is classified as pathogenic. (less)
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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: SCV000606639.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
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Pathogenic
(Jan 05, 2021)
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no assertion criteria provided
Method: clinical testing
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002086877.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
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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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Analysis of LDLR variants from homozygous FH patients carrying multiple mutations in the LDLR gene. | Jiang L | Atherosclerosis | 2017 | PMID: 28645073 |
The molecular basis of familial hypercholesterolemia in the Czech Republic: spectrum of LDLR mutations and genotype-phenotype correlations. | Tichý L | Atherosclerosis | 2012 | PMID: 22698793 |
Cardiovascular risk in relation to functionality of sequence variants in the gene coding for the low-density lipoprotein receptor: a study among 29,365 individuals tested for 64 specific low-density lipoprotein-receptor sequence variants. | Huijgen R | European heart journal | 2012 | PMID: 22390909 |
Molecular basis of autosomal dominant hypercholesterolemia: assessment in a large cohort of hypercholesterolemic children. | van der Graaf A | Circulation | 2011 | PMID: 21382890 |
Molecular spectrum of autosomal dominant hypercholesterolemia in France. | Marduel M | Human mutation | 2010 | PMID: 20809525 |
Molecular characterization of Polish patients with familial hypercholesterolemia: novel and recurrent LDLR mutations. | Chmara M | Journal of applied genetics | 2010 | PMID: 20145306 |
Genetic diagnosis of familial hypercholesterolemia using a DNA-array based platform. | Alonso R | Clinical biochemistry | 2009 | PMID: 19318025 |
Six novel mutations of the LDL receptor gene in FH kindred of Sicilian and Paraguayan descent. | Cefalù AB | International journal of molecular medicine | 2006 | PMID: 16465405 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Genetic characterization of Swedish patients with familial hypercholesterolemia: a heterogeneous pattern of mutations in the LDL receptor gene. | Lind S | Atherosclerosis | 2002 | PMID: 12052488 |
Intronic mutations at splice junctions in the low-density lipoprotein receptor gene. | Peeters AV | Molecular and cellular probes | 1999 | PMID: 10441197 |
An acceptor splice site mutation in intron 16 of the low density lipoprotein receptor gene leads to an elongated, internalization defective receptor. | Lombardi P | Atherosclerosis | 1993 | PMID: 8141835 |
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Text-mined citations for rs767790696 ...
HelpRecord 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.