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NM_000527.5(LDLR):c.1186+5G>A

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely pathogenic(2);Pathogenic(2);Uncertain significance(2)

Review status:
criteria provided, conflicting interpretations
Submissions:
7 (Most recent: Jan 7, 2021)
Last evaluated:
Nov 2, 2020
Accession:
VCV000251706.5
Variation ID:
251706
Description:
single nucleotide variant
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NM_000527.5(LDLR):c.1186+5G>A

Allele ID
246029
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
19p13.2
Genomic location
19: 11111644 (GRCh38) GRCh38 UCSC
19: 11222320 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000019.10:g.11111644G>A
NC_000019.9:g.11222320G>A
NM_000527.5:c.1186+5G>A MANE Select
... more HGVS
Protein change
-
Other names
-
Canonical SPDI
NC_000019.10:11111643:G:A
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
-
Links
ClinGen: CA10585344
LDLR-LOVD, British Heart Foundation: LDLR_000881
dbSNP: rs879254821
Varsome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Pathogenic/Likely pathogenic 2 criteria provided, multiple submitters, no conflicts Nov 2, 2020 RCV001039692.2
Conflicting interpretations of pathogenicity 5 criteria provided, conflicting interpretations Mar 30, 2017 RCV000237711.4

Clinical features observed in individuals with this variant

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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
LDLR Sufficient evidence for dosage pathogenicity No evidence available GRCh38
GRCh37
3087 3287

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Pathogenic
(Mar 25, 2016)
criteria provided, single submitter
Method: literature only
Familial hypercholesterolemia
(Autosomal dominant inheritance)
Allele origin: germline
LDLR-LOVD, British Heart Foundation
Accession: SCV000295266.2
Submitted: (Apr 20, 2016)
Evidence details
Publications
PubMed (2)
Likely pathogenic
(Mar 30, 2017)
criteria provided, single submitter
Method: clinical testing
Familial Hypercholesterolemia
Allele origin: germline
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille
Accession: SCV000583800.1
Submitted: (Mar 31, 2017)
Comment:
ACMG Guidelines: Likely Pathogenic (v)
Evidence details
Uncertain significance
(Mar 01, 2016)
criteria provided, single submitter
Method: research
Familial hypercholesterolemia
Allele origin: germline
Fundacion Hipercolesterolemia Familiar
Study: SAFEHEART
Accession: SCV000607568.1
Submitted: (Apr 20, 2017)
Evidence details
Uncertain significance
(Mar 01, 2016)
criteria provided, single submitter
Method: research
Familial hypercholesterolemia
Allele origin: germline
Iberoamerican FH Network
Accession: SCV000748141.1
Submitted: (Jul 28, 2017)
Comment:
Variant present in the database from Uruguay
Evidence details
Pathogenic
(Nov 02, 2020)
criteria provided, single submitter
Method: clinical testing
Familial hypercholesterolemia
Allele origin: germline
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001448367.1
Submitted: (Dec 02, 2020)
Evidence details
Publications
PubMed (4)
Comment:
Variant summary: LDLR c.1186+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly … (more)
Likely pathogenic
(Dec 24, 2019)
criteria provided, single submitter
Method: clinical testing
Familial hypercholesterolemia
Allele origin: germline
Invitae
Accession: SCV001203233.2
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (5)
Comment:
This sequence change falls in intron 8 of the LDLR gene. It does not directly change the encoded amino acid sequence of the LDLR protein, … (more)
Pathogenic
(-)
no assertion criteria provided
Method: research
Familial hypercholesterolemia
Allele origin: germline
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum
Accession: SCV000606343.1
Submitted: (Apr 25, 2017)
Evidence details

Functional evidence

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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 this variant

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Title Author Journal Year Link
Contribution of mutations in low density lipoprotein receptor (LDLR) and lipoprotein lipase (LPL) genes to familial combined hyperlipidemia (FCHL): a reappraisal by using a resequencing approach. Minicocci I Atherosclerosis 2015 PMID: 26342331
Inheritance pattern of familial hypercholesterolemia and markers of cardiovascular risk. Kusters DM Journal of lipid research 2013 PMID: 23833242
Functional characterization of splicing and ligand-binding domain variants in the LDL receptor. Etxebarria A Human mutation 2012 PMID: 21990180
Genetic diagnosis of familial hypercholesterolemia using a DNA-array based platform. Alonso R Clinical biochemistry 2009 PMID: 19318025
Femoral atherosclerosis in heterozygous familial hypercholesterolemia: influence of the genetic defect. Junyent M Arteriosclerosis, thrombosis, and vascular biology 2008 PMID: 18096825
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
Intronic mutations outside of Alu-repeat-rich domains of the LDL receptor gene are a cause of familial hypercholesterolemia. Amsellem S Human genetics 2002 PMID: 12436241
Statistical features of human exons and their flanking regions. Zhang MQ Human molecular genetics 1998 PMID: 9536098

Text-mined citations for rs879254821...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jun 14, 2021