ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.1586+5G>A
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.
Pathogenic(3); Likely pathogenic(9); Uncertain significance(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000527.5(LDLR):c.1586+5G>A
Variation ID: 251909 Accession: VCV000251909.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11113767 (GRCh38) [ NCBI UCSC ] 19: 11224443 (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 Apr 4, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000527.5:c.1586+5G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001195798.2:c.1586+5G>A intron variant NM_001195799.2:c.1463+5G>A intron variant NM_001195800.2:c.1082+5G>A intron variant NM_001195803.2:c.1205+5G>A intron variant NC_000019.10:g.11113767G>A NC_000019.9:g.11224443G>A NG_009060.1:g.29387G>A LRG_274:g.29387G>A LRG_274t1:c.1586+5G>A - Protein change
- Other names
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- Canonical SPDI
- NC_000019.10:11113766:G:A
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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
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00003
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
Help
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
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 |
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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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Conflicting interpretations of pathogenicity (11) |
criteria provided, conflicting classifications
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Apr 4, 2024 | RCV000237174.14 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Mar 27, 2023 | RCV000587894.7 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 28, 2023 | RCV001044315.6 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 15, 2018 | RCV002401938.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Aug 26, 2022 | RCV004017559.1 |
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
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
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
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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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: SCV000295512.2
First in ClinVar: Jul 29, 2016 Last updated: Sep 30, 2017 |
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
Observation 6:
Number of individuals with the variant: 1
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Uncertain significance
(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: SCV000503370.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Comment:
subjects mutated among 2600 FH index cases screened = 2
Number of individuals with the variant: 2
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Likely 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: SCV000583852.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016
Comment:
ACMG Guidelines: Likely Pathogenic (v)
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Number of individuals with the variant: 2
Clinical Features:
Hyperbetalipoproteinemia (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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Uncertain significance
(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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Fundacion Hipercolesterolemia Familiar
Study: SAFEHEART
Accession: SCV000607609.1 First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
Observation 1:
Comment on evidence:
%MAF(ExAC):0.003401
Observation 2:
Comment on evidence:
Htz patients' Epstein Barr virus transformed lymphocytes, RNA assays
Result:
skipping of exon 10 (p.Thr454_Gly529del)
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Uncertain significance
(Apr 25, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697204.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The LDLR c.1586+5G>A variant involves the alteration of a conserved intronic nucleotide that is 5 nucleotides away from the exon-intron junction. 4/5 splice … (more)
Variant summary: The LDLR c.1586+5G>A variant involves the alteration of a conserved intronic nucleotide that is 5 nucleotides away from the exon-intron junction. 4/5 splice prediction tools predict a significant impact on normal splicing and ESE finder predicts that the variant may cause an SRp55 ESE site to be introduced at the locus. One functional study has shown that the variant causes two aberrant splicing transcripts in several heterozygous patient cell lines and that the variant segregates with disease within two families, although several family members are discordant. This study also showed that LDL receptor was not properly trafficked to the cell surface in transfected COS7 cells (Jensen_CG_1999). However, a second functional study also detected aberrant splicing, but assessed LDL receptor protein function in heterozygous patient-derived lymphoblast cell lines and found that ~75% or greater of LDLR was at the cell surface and LDL was internalized similarly to controls, suggesting the variant transcripts do not have a significant biological impact (Holla_MGM_2009). Additionally, several studies have cited the variant in hypercholesterolemia patients, though cosegregation data is lacking in most cases. Based on the literature data, the variant may represent a mild mutation and may have a potentiated effect in compound heterozygosity with a truly pathogenic mutation, but have a less severe impact in heterozygous patients. This variant was found in the large control database ExAC at a frequency of 0.000034 (4/117662 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0010005). Multiple clinical diagnostic laboratories/reputable databases have classified this variant with conflicting interpretations, including likely pathogenic and uncertain significance. Taken together, this variant is classified as VUS until more conclusive family segregation data and/or control data can be assessed. (less)
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Uncertain significance
(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: SCV001432658.1
First in ClinVar: Sep 19, 2020 Last updated: Sep 19, 2020 |
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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Likely pathogenic
(Mar 27, 2023)
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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: SCV001789378.2
First in ClinVar: Aug 21, 2021 Last updated: Apr 09, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); While mRNA studies confirm the presence of one or more alternatively-spliced transcripts, functional studies at … (more)
Not observed at significant frequency in large population cohorts (gnomAD); While mRNA studies confirm the presence of one or more alternatively-spliced transcripts, functional studies at the protein level do not agree on the effect of this variant on receptor function (Jensen et al., 1999; Holla et al., 2009); Also known as c.1592+5 G>A; This variant is associated with the following publications: (PMID: 27578104, 27821657, 25463123, 19208450, 16250003, 17539906, 19446849, 31447099, 32793292, 17964958, 30710474, 7635461, 32977124, 32660911, 33740630, 34037665, 33418990, 34456049, 35913489, 31947532, 10668928) (less)
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Pathogenic
(Oct 28, 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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Invitae
Accession: SCV001208106.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024 |
Comment:
This sequence change falls in intron 10 of the LDLR gene. It does not directly change the encoded amino acid sequence of the LDLR protein. … (more)
This sequence change falls in intron 10 of the LDLR gene. It does not directly change the encoded amino acid sequence of the LDLR protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs781362878, gnomAD 0.02%). This variant has been observed in individuals with hypercholesterolemia (PMID: 7635461, 10668928, 17539906, 19208450, 19446849, 25463123). This variant is also known as c.1592+5G>A. ClinVar contains an entry for this variant (Variation ID: 251909). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of 10, but is expected to preserve the integrity of the reading-frame (PMID: 10668928, 19208450). This variant disrupts the c.1586+5 nucleotide in the LDLR gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 17964958; Invitae). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Feb 17, 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: SCV002581306.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS4, PM2_SUP, PP3
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Number of individuals with the variant: 1
Sex: male
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Likely pathogenic
(Apr 29, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV002762690.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
Comment:
The LDLR c.1586+5G>A variant, also known as c.1592+5G>A, occurs in a splice region and results in the substitution of a guanine at nucleotide position c.1586+5 … (more)
The LDLR c.1586+5G>A variant, also known as c.1592+5G>A, occurs in a splice region and results in the substitution of a guanine at nucleotide position c.1586+5 with an adenine. Across a selection of the available literature, the c.1586+5G>A variant has been identified in at least seven individuals with clinically diagnosed familial hypercholesterolemia and was shown to segregate with the disorder (Ekstrom et al. 1995; Jensen et al. 1999; Fouchier et al. 2005; Mollaki et al. 2016; Bertolini et al. 2020; Meshkov et al. 2020; Lamiquiz-Moneo et al. 2021; Leren et al. 2021; Sturm et al. 2021). Another variant at the same nucleotide position, has been reported as c.1592+5G>C in a heterozygous state in three individuals with familial hypercholesterolemia (Yang et al. 2007; Defesche et al. 2017). This variant is reported in the Genome Aggregation Database in six alleles at a frequency of 0.000196 in the South Asian population (version 2.1.1). Analysis of mRNA from patient cells with sequence analysis found that the c.1586+5G>A variant results in alternate RNA splicing mechanisms that cause the activation of a cryptic splice site within intron 10 or skipping of exon 10 and causes defects in receptor transport in vitro (Jensen et al. 1999). Based on the available evidence, the c.1586+5G>A variant is classified as likely pathogenic for familial hypercholesterolemia. (less)
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Pathogenic
(Oct 16, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV004358535.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This variant causes a G to A nucleotide substitution at the +5 position of intron 10 of the LDLR gene. Splice site prediction tools predict … (more)
This variant causes a G to A nucleotide substitution at the +5 position of intron 10 of the LDLR gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Molecular studies of the impact of this variant on RNA splicing demonstrated two aberrant mRNAs due to either in-frame skipping of exon 10 or the activation of a cryptic splice site in intron 10 inserting 66 intronic base pairs (PMID: 10668928). Additionally, this variant was shown to cause aberrant LDL receptor trafficking in transfected COS7 cells (PMID: 10668928). This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 7635461, 10668928, 16250003, 17539906, 19446849, 25463123, 31947532, 32660911, 32977124, 33418990, 34037665, 36960729). It has been shown that this variant segregates with disease in multiple affected individuals in one family (PMID: 10668928). This variant has been identified in 8/250846 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease (clinicalgenome.org). A different variant occurring at the same position, c.1586+5G>C, is known to be pathogenic (ClinVar variation ID: 440652), indicating that c.G nucleotide at this position is important for normal RNA splicing. Based on the available evidence, this variant is classified as Pathogenic. (less)
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Likely pathogenic
(Apr 04, 2024)
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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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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004810144.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
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Pathogenic
(Mar 30, 2023)
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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 Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812558.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
This sequence change in LDLR is an intronic variant located in intron 10 (also described as c.1592+5G>A). The highest population minor allele frequency in gnomAD … (more)
This sequence change in LDLR is an intronic variant located in intron 10 (also described as c.1592+5G>A). The highest population minor allele frequency in gnomAD v2.1 is 0.02% (6/30,588 alleles) in the South Asian population, which is lower than the credible allele frequency for this LDLR. This variant has been reported in at least 10 probands/families meeting a clinical diagnosis of familial hypercholesterolaemia and segregates with disease in multiple families (PMID: 7635461, 10668928, 19208450, 19446849, 25463123, 31345425, 33418990; ClinVar: SCV000503370.1, SCV000583852.1). The results from multiple in silico splicing predictors (SpliceAI, MaxEntScan, NNSplice) indicate that this variant may impact splicing by disrupting the donor splice site of intron 10 of LDLR. This prediction is confirmed by RT-PCR of EBV-transformed lymphocytes. The assay demonstrated that the variant impacts splicing by causing in-frame exon 10 skipping and 66 bp insertion of intron 10 through cryptic donor site activation (PMID: 10668928, 19208450). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PS4, PP1_Strong, PS3_Supporting, PM2_Supporting, PP3. (less)
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Likely Pathogenic
(Aug 28, 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: SCV004822567.1
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 causes a G to A nucleotide substitution at the +5 position of intron 10 of the LDLR gene. Splice site prediction tools predict … (more)
This variant causes a G to A nucleotide substitution at the +5 position of intron 10 of the LDLR gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Molecular studies of the impact of this variant on RNA splicing demonstrated two aberrant mRNAs due to either in-frame skipping of exon 10 or the activation of a cryptic splice site in intron 10 inserting 66 intronic base pairs (PMID: 10668928). Additionally, this variant was shown to cause aberrant LDL receptor trafficking in transfected COS7 cells (PMID: 10668928). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 7635461, 10668928, 16250003, 17539906, 19446849, 25463123, 32660911). This variant has also been observed in compound heterozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 31947532, 32977124), indicating that this variant contributes to disease. It has been shown that this variant segregates with disease in multiple affected individuals in one family (PMID: 10668928). This variant has been identified in 8/250846 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
Number of individuals with the variant: 3
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Likely Pathogenic
(Aug 26, 2022)
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criteria provided, single submitter
Method: clinical testing
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Homozygous familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848107.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The c.1586+5G>A variant in LDLR has been reported in 7 individuals with familial hypercholesterolemia (FH) and segregated with disease in at least 7 affected relatives … (more)
The c.1586+5G>A variant in LDLR has been reported in 7 individuals with familial hypercholesterolemia (FH) and segregated with disease in at least 7 affected relatives from 2 families (Ekstrom 1995, Jensen 1999, Fouchier 2005, Taylor 2007, Guardamagna 2009, Mollaki 2014). Additionally, this variant has been identified in 6/30752 South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/) and is present in ClinVar (Variation ID: 251909). Please note that for diseases with clinical variability, reduced penetrance, or recessive inheritance, pathogenic variants may be present at a low frequency in the general population. In vitro functional studies provide some evidence that the c.1586+5G>A variant may impact protein function (Jensen 1999. This variant is located in the 5' splice region. Computational tools do suggest an impact to splicing. In summary, although additional studies are required to fully establish its clinical significance, the c.1586+5G>A variant is likely pathogenic for FH in an autosomal dominant manner based on cased observations, segregation studies, functional and computational evidence. The ACMG/AMP Criteria applied: PP1_Strong, PS4_Moderate, PP3, PS3_Supporting. (less)
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Likely pathogenic
(Jan 15, 2018)
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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: SCV002705210.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.1586+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 10 in the LDLR gene. This alteration has been … (more)
The c.1586+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 10 in the LDLR gene. This alteration has been detected in individuals with confirmed familial hypercholesterolemia (FH) and in FH cohorts (Fouchier SW et al. Hum. Mutat., 2005 Dec;26:550-6; Taylor A et al. Clin. Genet., 2007 Jun;71:561-8; Guardamagna O et al. J. Pediatr., 2009 Aug;155:199-204.e2; Mollaki V et al. Atherosclerosis, 2014 Dec;237:798-804). Segregation with hypercholesterolemia has been observed with this alteration (reported as c.1592+5G>A); of note, in at least one family some heterozygotes had normal or near normal cholesterol levels at the time of testing (Jensen HK et al. Clin. Genet., 1999 Nov;56:378-88). RNA splicing studies have revealed exon-skipping and use of a cryptic donor site in mutant transcripts, while functional studies demonstrated some reduction in LDLR activity and conflicting membrane-trafficking results (Jensen HK et al. Clin. Genet., 1999 Nov;56:378-88; Holla ØL et al. Mol. Genet. Metab., 2009 Apr;96:245-52). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. Based on the majority of available evidence to date, this variant is likely to be 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: SCV000606461.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
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Pathogenic
(Dec 11, 2017)
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no assertion criteria provided
Method: provider interpretation
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not provided
Affected status: unknown
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000925125.1
First in ClinVar: Jul 01, 2019 Last updated: Jul 01, 2019 |
Comment:
c.1586+5G>A in intron 10 of the LDLR gene (NM_00527; chr19-11224443-G-A) SCICD Classification: pathogenic variant based on strong case data, strong segregation data and strong functional … (more)
c.1586+5G>A in intron 10 of the LDLR gene (NM_00527; chr19-11224443-G-A) SCICD Classification: pathogenic variant based on strong case data, strong segregation data and strong functional data. We do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: LDLR: LDL receptors are located on the surface of the liver and play an important role in LDL recycling. Pathogenic variants in LDLR account for 80% of cases of familial hypercholesterolemia. Both missense and truncating/frameshift variants can be pathogenic. Case data (not including our patient): at least 25 cases, plus other family members. · ClinVar: § LDLR-LOVD, British Heart Foundation - likely pathogenic - 2 out of 2600 patients with FH have this variant § Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix - VUS § U4M - Lille University & CHRU Lille,Université Lille 2 - CHRU de Lille - likely pathogenic § Fundacion Hipercolesterolemia Familiar - VUS § Never seen at Invitae § Color Genomics has this variant in their "John Doe" report: they indicate that many algorithms predict a significant impact on the intron 10 donor · Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum - pathogenic · Cases in the literature: · Yang et al 2007: 87 Taiwanese individuals with FH from 30 unrelated families: seen in 2 families. Authors report that this variant may result in the skipping of exon 10. This variant segregated with disease in family members; however, the number of family members with which it segregates is unknown. · Ekström et al 1994: this variant (noted as c.1596+5G>A in this paper) was detected in 1 out of 7 children with FH. · Fouchier et al 2005: 1 out of 325 patients in the Dutch cohort · Taylor et al 2007: Found this variant in one out of 400 patients with FH. This particular patient had possible FH. · Guardamagna et al 2009: This variant was seen in one patient of the following cohort: 264 children from 201 families, 148 affected parents and 100 unaffected siblings. · Mollaki et al 2014: Variant detected in 1 out of 561 patients from 262 families · Jensen et al 1999: This variant is known as c.1596+5G>A in this paper. This variant was present in a 36yo Danish man presenting with tendon xanthomas, severe CAD, CABG at 24yo and very high LDL cholesterol. This man had another variant as well - p.T383P. This variant segregated with disease in his family members (pedigree A, FH-DK 8). Another family had only this variant and it segregated with disease. From the first family, this variant segregated with 8 affected individuals. From the second family, this variant segregated in 4 individuals. Segregation data: See above, Jensen et al 1999 Functional data: Jenner et 1999: sequence analysis of cDNA indicates that either i) a cryptic splice site is activated or ii) exon 10 is skipped: i) the donor splice site at the +5 position is activated to create a cryptic splice site which results in an in-frame insertion of 22 amino acids; ii) in-frame deletion of 75 amino acids in the EGF precursor homology domain of the LDL receptor protein. The authors predicted about 50% of these variants were spliced correctly, and 50% spliced incorrectly. To measure the amount of LDL receptor protein on the surface of the cells, fluorescence was used. Fluorescence of both of these mutant cell lines was markedly reduced in both of these cell lines compared to wildtype. Splice data (splice variants only): Buratti et al 2007: "...point mutations leading to cryptic 5' splice site activation were most common in the first intron nucleotide, followed by the fifth nucleotide. Substititons at position +5 were exclusively G>A transitions... The frequency of point mutations at position +5 was significantly higher than observed in[HGMD] suggesting that alterations of this position are particularly prone to aberrant splicing, possibly due to a requirement for sequential interactions with U1 and U6 snRNAs." Functional data above by Jensen and colleagues corroborates predictions that this variant impacts splicing. Conservation data: The G at position c.1586+5 is conserved among species. Population data: Highest MAF in South Asian population: 0.0195%. The variant was reported online in 8 of 122,672 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 6 of 15,376 individuals of South Asian descent (MAF=0.0195%) and 2 of 55,674 individuals of European descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. (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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Genetic Identification of Homozygous Familial Hypercholesterolemia by Long-Read Sequencing Among Patients With Clinically Diagnosed Heterozygous Familial Hypercholesterolemia. | Chaudhry A | Circulation. Genomic and precision medicine | 2023 | PMID: 36960729 |
Limited-Variant Screening vs Comprehensive Genetic Testing for Familial Hypercholesterolemia Diagnosis. | Sturm AC | JAMA cardiology | 2021 | PMID: 34037665 |
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 |
The LDLR, APOB, and PCSK9 Variants of Index Patients with Familial Hypercholesterolemia in Russia. | Meshkov A | Genes | 2021 | PMID: 33418990 |
Diagnostic yield of sequencing familial hypercholesterolemia genes in individuals with primary hypercholesterolemia. | Lamiquiz-Moneo I | Revista espanola de cardiologia (English ed.) | 2021 | PMID: 32660911 |
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 |
Risk of Premature Atherosclerotic Disease in Patients With Monogenic Versus Polygenic Familial Hypercholesterolemia. | Trinder M | Journal of the American College of Cardiology | 2019 | PMID: 31345425 |
Efficacy of alirocumab in 1191 patients with a wide spectrum of mutations in genes causative for familial hypercholesterolemia. | Defesche JC | Journal of clinical lipidology | 2017 | PMID: 28964736 |
The UCL low-density lipoprotein receptor gene variant database: pathogenicity update. | Leigh S | Journal of medical genetics | 2017 | PMID: 27821657 |
Genetic causes of monogenic familial hypercholesterolemia in the Greek population: Lessons, mistakes, and the way forward. | Mollaki V | Journal of clinical lipidology | 2016 | PMID: 27578104 |
Familial Hypercholesterolemia in Greek children and their families: genotype-to-phenotype correlations and a reconsideration of LDLR mutation spectrum. | Mollaki V | Atherosclerosis | 2014 | PMID: 25463123 |
The type of LDLR gene mutation predicts cardiovascular risk in children with familial hypercholesterolemia. | Guardamagna O | The Journal of pediatrics | 2009 | PMID: 19446849 |
Effects of intronic mutations in the LDLR gene on pre-mRNA splicing: Comparison of wet-lab and bioinformatics analyses. | Holla ØL | Molecular genetics and metabolism | 2009 | PMID: 19208450 |
LDLR and ApoB are major genetic causes of autosomal dominant hypercholesterolemia in a Taiwanese population. | Yang KC | Journal of the Formosan Medical Association = Taiwan yi zhi | 2007 | PMID: 17964958 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Multiplex ARMS analysis to detect 13 common mutations in familial hypercholesterolaemia. | Taylor A | Clinical genetics | 2007 | PMID: 17539906 |
Update of the molecular basis of familial hypercholesterolemia in The Netherlands. | Fouchier SW | Human mutation | 2005 | PMID: 16250003 |
Normolipidemia and hypercholesterolemia in persons heterozygous for the same 1592 + 5G --> A splice site mutation in the low-density lipoprotein receptor gene. | Jensen HK | Clinical genetics | 1999 | PMID: 10668928 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
An efficient screening procedure detecting six novel mutations in the LDL receptor gene in Swedish children with hypercholesterolemia. | Ekström U | Human genetics | 1995 | PMID: 7635461 |
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Text-mined citations for rs781362878 ...
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.