ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.2311+1G>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_000527.5(LDLR):c.2311+1G>T
Variation ID: 252274 Accession: VCV000252274.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11123345 (GRCh38) [ NCBI UCSC ] 19: 11234021 (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 May 6, 2020 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000527.5:c.2311+1G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001195798.2:c.2311+1G>T splice donor NM_001195799.2:c.2188+1G>T splice donor NM_001195800.2:c.1807+1G>T splice donor NM_001195803.2:c.1777+1G>T splice donor NC_000019.10:g.11123345G>T NC_000019.9:g.11234021G>T NG_009060.1:g.38965G>T LRG_274:g.38965G>T LRG_274t1:c.2311+1G>T - Protein change
- Other names
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- Canonical SPDI
- NC_000019.10:11123344:G: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 |
4070 | 4346 |
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
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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Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Mar 23, 2020 | RCV000237602.11 | |
Pathogenic (1) |
criteria provided, single submitter
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May 6, 2020 | RCV001385153.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 27, 2017 | RCV002446479.2 |
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
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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
Help
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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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: SCV000295942.2
First in ClinVar: Jul 29, 2016 Last updated: May 03, 2018 |
Number of individuals with the variant: 1
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Pathogenic
(Dec 16, 2016)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
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Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix
Accession: SCV000503479.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Comment:
subjects mutated among 2600 FH index cases screened = 2 , family member = 1 / FH Italia, 12% LDLR activity
Number of individuals with the variant: 2
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Pathogenic
(Mar 30, 2017)
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criteria provided, single submitter
Method: clinical testing
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Familial Hypercholesterolemia
Affected status: yes
Allele origin:
germline
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U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille
Accession: SCV000583941.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016
Comment:
ACMG Guidelines: Pathogenic (i)
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Number of individuals with the variant: 1
Clinical Features:
Hyperbetalipoproteinemia (present) , Hypercholesterolemia (present)
Indication for testing: Familial Hypercholesterolemia
Geographic origin: France
Comment on evidence:
Dutch Lipid Clinic Scoring : Definite FH
Secondary finding: no
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Pathogenic
(Mar 01, 2016)
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criteria provided, single submitter
Method: research
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
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Laboratory of Genetics and Molecular Cardiology, University of São Paulo
Study: HipercolBrasil
Accession: SCV000588647.1 First in ClinVar: Aug 13, 2017 Last updated: Aug 13, 2017 |
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Pathogenic
(Mar 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002017128.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(May 06, 2020)
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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: SCV001584913.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
Disruption of this splice site has been observed in individual(s) with familial hypercholesterolemia (PMID: 7545204, 16389549, 20809525). ClinVar contains an entry for this variant (Variation … (more)
Disruption of this splice site has been observed in individual(s) with familial hypercholesterolemia (PMID: 7545204, 16389549, 20809525). ClinVar contains an entry for this variant (Variation ID: 252274). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 15 of the LDLR gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants 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). (less)
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Pathogenic
(Nov 27, 2017)
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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: SCV002735337.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.2311+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 15 of the LDLR gene. This mutation was … (more)
The c.2311+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 15 of the LDLR gene. This mutation was reported in two apparently unrelated individuals with familial hypercholesterolemia, and was described to segregate with the disease in their families (Marduel M et al. Hum. Mutat., 2010 Nov;31:E1811-24). In addition to the clinical data presented in the literature, 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. As such, this alteration is classified as a disease-causing mutation. (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: SCV000606630.1
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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Analysis of LDLR variants from homozygous FH patients carrying multiple mutations in the LDLR gene. | Jiang L | Atherosclerosis | 2017 | PMID: 28645073 |
Molecular spectrum of autosomal dominant hypercholesterolemia in France. | Marduel M | Human mutation | 2010 | PMID: 20809525 |
Mutational analysis in UK patients with a clinical diagnosis of familial hypercholesterolaemia: relationship with plasma lipid traits, heart disease risk and utility in relative tracing. | Humphries SE | Journal of molecular medicine (Berlin, Germany) | 2006 | PMID: 16389549 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Occurrence of multiple aberrantly spliced mRNAs of the LDL-receptor gene upon a donor splice site mutation that causes familial hypercholesterolemia (FHBenevento). | Lelli N | Journal of lipid research | 1995 | PMID: 7545204 |
Text-mined citations for this variant ...
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.