ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.313_313+1del
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.313_313+1del
Variation ID: 226316 Accession: VCV000226316.12
- Type and length
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Deletion, 2 bp
- Location
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Cytogenetic: 19p13.2 19: 11102786-11102787 (GRCh38) [ NCBI UCSC ] 19: 11213462-11213463 (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 May 22, 2016 Apr 20, 2024 Jun 14, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000527.5:c.313_313+1del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_000527.4(LDLR):c.313_313+1delCG NM_000527.4:c.313_313+1delCG NM_001195798.2:c.313_313+1del splice donor NM_001195799.2:c.191-2434_191-2433del intron variant NM_001195800.2:c.313_313+1del splice donor NM_001195803.2:c.313_313+1del splice donor NC_000019.10:g.11102786_11102787del NC_000019.9:g.11213462_11213463del NG_009060.1:g.18406_18407del LRG_274:g.18406_18407del LRG_274t1:c.313_313+1del - Protein change
- Other names
- FH Lille
- Canonical SPDI
- NC_000019.10:11102785:CG:
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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
Help
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 |
4017 | 4288 |
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/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Feb 2, 2022 | RCV000211607.11 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 22, 2020 | RCV001249011.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 14, 2022 | RCV002469073.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 11, 2019 | RCV004017501.1 |
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
Help
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
(-)
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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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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000987703.1
First in ClinVar: Sep 08, 2019 Last updated: Sep 08, 2019 |
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Likely pathogenic
(Jan 22, 2020)
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criteria provided, single submitter
Method: curation
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Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001422858.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 01, 2022 |
Comment:
The c.313_313+1delCG variant in LDLR has been reported in 1 Australian and 1 French individual with familial hypercholesterolemia (PMID: 22883975, 1301956), and was absent from … (more)
The c.313_313+1delCG variant in LDLR has been reported in 1 Australian and 1 French individual with familial hypercholesterolemia (PMID: 22883975, 1301956), and was absent from large population studies. This variant has also been reported in ClinVar as pathogenic (Variation ID: 226316). In vitro functional studies provide some evidence that the c.313_313+1delCG variant may slightly impact protein function (PMID: 1301956). However, these types of assays may not accurately represent biological function. This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence, deletes the last base of the exon inducing a frameshift, and is predicted to cause altered splicing leading to an abnormal or absent protein. Heterozygous loss of function of the LDLR gene is an established disease mechanism in familial hypercholesterolemia. There is an in-frame cryptic splice site within 6 basepairs of the intron-exon boundary that could result in a rescued transcript and may maintain function of LDLR. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3_supporting, PS4_supporting, PVS1_moderate, PM2 (Richards 2015). (less)
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Pathogenic
(Jun 14, 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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GeneDx
Accession: SCV002765862.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect as cell cultures from a homozygous patient show … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect as cell cultures from a homozygous patient show 2-5% residual LDL receptor activity (Hobbs et al., 1992); Canonical splice site variant expected to result in aberrant splicing; Deletions involving coding exons of this gene are a known mechanism of disease (HGMD); Also known as FH Lille; This variant is associated with the following publications: (PMID: 1301956, 33087929, 22883975) (less)
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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: SCV000294601.2
First in ClinVar: Jul 29, 2016 Last updated: Sep 09, 2017 |
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: SCV000503130.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Comment:
subjects mutated among 2600 FH index cases screened = 2 , family members = 2
Number of individuals with the variant: 2
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Pathogenic
(Mar 01, 2016)
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criteria provided, single submitter
Method: curation, literature only
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Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: not applicable, unknown
Allele origin:
germline,
not applicable
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Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge
Accession: SCV000599324.1
First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017 |
Observation 1: Observation 2:
Comment on evidence:
Assay Description:Hmz patients' fibroblasts, 125I-LDL assays
Result:
2-5% LDLR activity
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Pathogenic
(Mar 30, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
(Codominant)
Affected status: yes
Allele origin:
germline
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U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille
Accession: SCV000583653.2
First in ClinVar: Jul 29, 2016 Last updated: Mar 12, 2022
Comment:
ACMG Guidelines: Pathogenic (i)
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Comment:
Updated according to ClinGen VCEP Guidelines (2022) for LDLR variant classification in FH (PMID: 34906454). This frameshift mutation is estimated to generate truncated protein products … (more)
Updated according to ClinGen VCEP Guidelines (2022) for LDLR variant classification in FH (PMID: 34906454). This frameshift mutation is estimated to generate truncated protein products deprived of most of their functional domains (PVS1). In addition, this deletion abolishes the canonical donor splice site of intron 3, without potentially creating any alternate donor splice site in close vicinity (PP3). It was shown by in-vitro studies (PS3 moderate) to abolish protein expression in homozygous carriers (FH Lille Allele). Mutation recurrently causing FH diagnosed by validated clinical criteria reported in multiple Disease Specific Databases for several decades (PS4) . Absent from Large General Population Databases (PM2 Strong). More than 10 index cases from the Lille registry had a clinical scoring of Definite FH (DLCN Score >8). This clinical scoring level is highly specific (90%) for a carrier status of a pathogenic LDLR mutation causative of FH (PP4 Strong). (less)
Number of individuals with the variant: 14
Clinical Features:
Increased LDL cholesterol concentration (present) , Hypercholesterolemia (present)
Indication for testing: Familial Hypercholesterolemia
Sex: mixed
Geographic origin: France
Comment on evidence:
Dutch Lipid Clinic Scoring : Definite FH
Secondary finding: no
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Likely pathogenic
(Feb 02, 2022)
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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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MGZ Medical Genetics Center
Accession: SCV002580841.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PVS1_STR, PS4_MOD, PS3_SUP, PM2_SUP
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Number of individuals with the variant: 1
Sex: female
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Pathogenic
(Oct 11, 2019)
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criteria provided, single submitter
Method: clinical testing
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Homozygous familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004847785.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The c.313_313+1delCG variant in LDLR has been reported in 2 individuals with hypercholesterolemia (Hobbs 1992, Hooper 2012). It was absent from large population studies. This … (more)
The c.313_313+1delCG variant in LDLR has been reported in 2 individuals with hypercholesterolemia (Hobbs 1992, Hooper 2012). It was absent from large population studies. This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. An in vitro study supports an impact on splicing (Hobbs 1992). Loss of function of the LDLR gene is an established disease mechanism in autosomal dominant familial hypercholesterolemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant familial hypercholesterolemia. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Supporting. (less)
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Pathogenic
(Jul 09, 2008)
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no assertion criteria provided
Method: clinical testing
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Familial hypercholesterolemia
Affected status: yes
Allele origin:
germline
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Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital
Accession: SCV000268553.1
First in ClinVar: May 22, 2016 Last updated: May 22, 2016 |
Number of individuals with the variant: 1
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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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The Clinical Genome Resource (ClinGen) Familial Hypercholesterolemia Variant Curation Expert Panel consensus guidelines for LDLR variant classification. | Chora JR | Genetics in medicine : official journal of the American College of Medical Genetics | 2022 | PMID: 34906454 |
Genetic analysis of familial hypercholesterolaemia in Western Australia. | Hooper AJ | Atherosclerosis | 2012 | PMID: 22883975 |
Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. | Hobbs HH | Human mutation | 1992 | PMID: 1301956 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/7737e618-03f9-4ef4-8615-cf4973a4c145 | - | - | - | - |
Text-mined citations for rs875989896 ...
HelpRecord last updated May 08, 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.