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NM_000527.5(LDLR):c.1359-5C>G

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely pathogenic(2);Pathogenic(1);Uncertain significance(4)

Review status:
criteria provided, conflicting interpretations
Submissions:
7 (Most recent: Aug 17, 2021)
Last evaluated:
Mar 22, 2021
Accession:
VCV000251808.9
Variation ID:
251808
Description:
single nucleotide variant
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NM_000527.5(LDLR):c.1359-5C>G

Allele ID
246122
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
19p13.2
Genomic location
19: 11113530 (GRCh38) GRCh38 UCSC
19: 11224206 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
LRG_274:g.29150C>G
LRG_274t1:c.1359-5C>G
NC_000019.10:g.11113530C>G
... more HGVS
Protein change
-
Other names
-
Canonical SPDI
NC_000019.10:11113529:C:G
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00006
Links
ClinGen: CA10585422
LDLR-LOVD, British Heart Foundation: LDLR_000192
dbSNP: rs531005522
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Uncertain significance 1 criteria provided, single submitter Jan 27, 2021 RCV000844742.2
Likely pathogenic 1 criteria provided, single submitter Mar 22, 2021 RCV001568174.3
Conflicting interpretations of pathogenicity 3 criteria provided, conflicting interpretations Oct 12, 2017 RCV000238316.4
Conflicting interpretations of pathogenicity 2 criteria provided, conflicting interpretations Dec 4, 2019 RCV001052016.2
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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
3093 3293
MIR6886 - - - GRCh38 - 40

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: SCV000295389.2
Submitted: (Apr 20, 2016)
Evidence details
Publications
PubMed (1)
Uncertain significance
(Mar 01, 2016)
criteria provided, single submitter
Method: research
Familial hypercholesterolemia
Allele origin: germline
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge
Accession: SCV000322946.1
Submitted: (Oct 14, 2016)
Evidence details
Comment:
0/75 normolipidaemic Portuguese controls
Uncertain significance
(Jan 27, 2021)
criteria provided, single submitter
Method: clinical testing
not specified
(Autosomal dominant inheritance)
Allele origin: germline
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine
Accession: SCV000731830.3
Submitted: (May 27, 2021)
Evidence details
Publications
PubMed (4)
Comment:
Variant classified as Uncertain Significance - Favor Pathogenic. The c.1359-5G>C variant in LDLR has been reported in 2 Portuguese individuals with Familial hypercholesterolemia (FH) and … (more)
Uncertain significance
(Dec 04, 2019)
criteria provided, single submitter
Method: clinical testing
Familial hypercholesterolemia
Allele origin: germline
Invitae
Accession: SCV001216204.1
Submitted: (Feb 06, 2020)
Evidence details
Publications
PubMed (1)
Comment:
This sequence change falls in intron 9 of the LDLR gene. It does not directly change the encoded amino acid sequence of the LDLR protein. … (more)
Uncertain significance
(Oct 12, 2017)
criteria provided, single submitter
Method: clinical testing
Familial hypercholesterolemia 1
Allele origin: germline
Illumina Clinical Services Laboratory,Illumina
Accession: SCV001286369.1
Submitted: (Feb 20, 2020)
Evidence details
Publications
PubMed (4)
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
Likely pathogenic
(Nov 15, 2019)
criteria provided, single submitter
Method: clinical testing
Familial hypercholesterolemia
Allele origin: germline
Color Health, Inc
Accession: SCV001347905.1
Submitted: (May 19, 2020)
Comment:
This variant causes a C>G nucleotide substitution at the -5 position of intron 9 of the LDLR gene. A transcriptional study using RNA from a … (more)
Evidence details
Likely pathogenic
(Mar 22, 2021)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV001791999.1
Submitted: (Aug 17, 2021)
Evidence details
Comment:
Not observed at a significant frequency in large population cohorts (Lek et al., 2016) This variant is associated with the following publications: (PMID: 31447099, 24627126, … (more)

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
Variable expression and penetrance in Portuguese families with Familial Hypercholesterolemia with mild phenotype. Gaspar IM Atherosclerosis. Supplements 2019 PMID: 30876530
The UCL low-density lipoprotein receptor gene variant database: pathogenicity update. Leigh S Journal of medical genetics 2017 PMID: 27821657
Cardiovascular risk assessment of dyslipidemic children: analysis of biomarkers to identify monogenic dyslipidemia. Medeiros AM Journal of lipid research 2014 PMID: 24627126
Detection of variations and identifying genomic breakpoints for large deletions in the LDLR by Ion Torrent semiconductor sequencing. Faiz F Atherosclerosis 2013 PMID: 24075752
Low-density lipoprotein receptor gene familial hypercholesterolemia variant database: update and pathological assessment. Usifo E Annals of human genetics 2012 PMID: 22881376
Genetic diagnosis of familial hypercholesterolaemia: the importance of functional analysis of potential splice-site mutations. Bourbon M Journal of medical genetics 2009 PMID: 19411563

Text-mined citations for rs531005522...

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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 Nov 27, 2021