ClinVar Genomic variation as it relates to human health
NC_000019.10:g.(?_11102644)_(11107534_?)del
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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NC_000019.10:g.(?_11102644)_(11107534_?)del
Variation ID: 584079 Accession: VCV000584079.6
- Type and length
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Deletion, 4,891 bp
- Location
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Cytogenetic: 19p13.2 19: 11102644-11107534 (GRCh38) [ NCBI UCSC ] 19: 11213320-11218210 (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 Oct 10, 2018 Nov 11, 2023 Nov 21, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNC_000019.10:g.(?_11102644)_(11107534_?)del NC_000019.9:g.(?_11213320)_(11218210_?)del - Protein change
- Other names
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- Canonical SPDI
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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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- Links
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 |
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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Pathogenic (1) |
criteria provided, single submitter
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Apr 23, 2018 | RCV000708285.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 21, 2021 | RCV001861928.4 |
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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Pathogenic
(Apr 23, 2018)
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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: SCV000837395.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
Comment:
This variant is an in-frame deletion of the genomic region encompassing exons 3-6 of the LDLR gene. It preserves the integrity of the reading frame. … (more)
This variant is an in-frame deletion of the genomic region encompassing exons 3-6 of the LDLR gene. It preserves the integrity of the reading frame. Similar deletions of exons 3-6 have been reported to segregate with familial hypercholesterolemia in a family and have been reported in unrelated individuals affected with this condition (PMID: 1863993, 23375686, 17399720, 16250003, 19538517). This variant affects an LDLRA domain of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). While functional studies have not been performed to directly test the effect of this variant on LDLR protein function, this suggests that disruption of this region of the protein is causative of disease. Several different missense substitutions (p.Cys116Arg, p.Asp266Glu, p.Cys313Tyr) have been determined to be pathogenic (PMID: 11668640, 10634824, 25545329, 1301956, 20663204, 22698793, 9259195, 9698020, 11810272) in this deleted region. This suggests that exons 3-6 are critical for LDLR protein function and that this deletion may also be pathogenic. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 21, 2021)
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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: SCV002176643.3
First in ClinVar: Mar 28, 2022 Last updated: Nov 11, 2023 |
Comment:
This variant is a gross deletion of the genomic region encompassing exon(s) 3-6 of the LDLR gene. This variant would be expected to be in-frame, … (more)
This variant is a gross deletion of the genomic region encompassing exon(s) 3-6 of the LDLR gene. This variant would be expected to be in-frame, preserving the integrity of the reading frame. A similar copy number variant has been observed in individuals with familial hypercholesterolemia (PMID: 1863993, 16250003, 17399720, 19538517, 23375686). It has also been observed to segregate with disease in related individuals. This variant affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). This variant disrupts a region of the LDLR protein in which other variant(s) (p.Cys95Gly, p.Cys116Arg, p.Asp266Glu, p.Cys313Tyr) have been determined to be pathogenic (PMID: 1301956, 9259195, 9698020, 10634824, 11668640, 11810272, 20663204, 22698793, 25545329). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as 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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Activity-associated effect of LDL receptor missense variants located in the cysteine-rich repeats. | Etxebarria A | Atherosclerosis | 2015 | PMID: 25545329 |
Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. | Bertolini S | Atherosclerosis | 2013 | PMID: 23375686 |
The molecular basis of familial hypercholesterolemia in the Czech Republic: spectrum of LDLR mutations and genotype-phenotype correlations. | Tichý L | Atherosclerosis | 2012 | PMID: 22698793 |
Genomic characterization of large rearrangements of the LDLR gene in Czech patients with familial hypercholesterolemia. | Goldmann R | BMC medical genetics | 2010 | PMID: 20663204 |
Multiplex ligation-dependent probe amplification analysis to screen for deletions and duplications of the LDLR gene in patients with familial hypercholesterolaemia. | Taylor A | Clinical genetics | 2009 | PMID: 19538517 |
Update and analysis of the University College London low density lipoprotein receptor familial hypercholesterolemia database. | Leigh SE | Annals of human genetics | 2008 | PMID: 18325082 |
Two new large deletions in the low density lipoprotein receptor (LDLR) gene not revealed by PCR-based molecular diagnosis of familial hypercholesterolemia. | Bernier L | Atherosclerosis | 2008 | PMID: 17399720 |
Update of the molecular basis of familial hypercholesterolemia in The Netherlands. | Fouchier SW | Human mutation | 2005 | PMID: 16250003 |
The molecular basis of familial hypercholesterolemia in The Netherlands. | Fouchier SW | Human genetics | 2001 | PMID: 11810272 |
Molecular genetics of familial hypercholesterolemia in Spain: Ten novel LDLR mutations and population analysis. | García-García AB | Human mutation | 2001 | PMID: 11668640 |
Influence of beta(0)-thalassemia on the phenotypic expression of heterozygous familial hypercholesterolemia : a study of patients with familial hypercholesterolemia from Sardinia. | Deiana L | Arteriosclerosis, thrombosis, and vascular biology | 2000 | PMID: 10634824 |
Low frequency of the common Norwegian and Finnish LDL-receptor mutations in Swedish patients with familial hypercholesterolaemia. | Lind S | Journal of internal medicine | 1998 | PMID: 9698020 |
Spectrum of LDL receptor gene mutations in heterozygous familial hypercholesterolemia. | Day IN | Human mutation | 1997 | PMID: 9259195 |
Three-dimensional structure of a cysteine-rich repeat from the low-density lipoprotein receptor. | Daly NL | Proceedings of the National Academy of Sciences of the United States of America | 1995 | PMID: 7603991 |
Disulfide bridges of a cysteine-rich repeat of the LDL receptor ligand-binding domain. | Bieri S | Biochemistry | 1995 | PMID: 7548065 |
Structures and functions of multiligand lipoprotein receptors: macrophage scavenger receptors and LDL receptor-related protein (LRP). | Krieger M | Annual review of biochemistry | 1994 | PMID: 7979249 |
Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. | Hobbs HH | Human mutation | 1992 | PMID: 1301956 |
DNA deletions in the low density lipoprotein (LDL) receptor gene in Danish families with familial hypercholesterolemia. | Rüdiger NS | Clinical genetics | 1991 | PMID: 1863993 |
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Text-mined citations for this variant ...
HelpRecord last updated Nov 11, 2023
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.