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NM_000527.5(LDLR):c.1463T>C (p.Ile488Thr)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely pathogenic(3);Uncertain significance(1)

Review status:
criteria provided, conflicting interpretations
Submissions:
5 (Most recent: Mar 28, 2019)
Last evaluated:
Sep 26, 2018
Accession:
VCV000251857.2
Variation ID:
251857
Description:
single nucleotide variant
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NM_000527.5(LDLR):c.1463T>C (p.Ile488Thr)

Allele ID
246171
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
19p13.2
Genomic location
19: 11113639 (GRCh38) GRCh38 UCSC
19: 11224315 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000019.10:g.11113639T>C
NC_000019.9:g.11224315T>C
NG_009060.1:g.29259T>C
... more HGVS
Protein change
I488T, I361T, I320T, I447T
Other names
-
Canonical SPDI
NC_000019.10:11113638:T:C
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
-
Links
ClinGen: CA10585467
LDLR-LOVD, British Heart Foundation: LDLR_000799
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Likely pathogenic 4 criteria provided, multiple submitters, no conflicts Mar 25, 2016 RCV000238089.7
Uncertain significance 1 criteria provided, single submitter Sep 26, 2018 RCV000791391.1
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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

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Likely 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: SCV000295448.2
Submitted: (Apr 20, 2016)
Evidence details
Publications
PubMed (1)
Likely pathogenic
(Mar 01, 2016)
criteria provided, single submitter
Method: research
Familial hypercholesterolemia
(Autosomal dominant inheritance)
Allele origin: germline
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge
Accession: SCV000322955.1
Submitted: (Oct 14, 2016)
Evidence details
Comment:
0/208 non-FH alleles
Likely pathogenic
(Mar 01, 2016)
criteria provided, single submitter
Method: research
Familial hypercholesterolemia
(Autosomal dominant inheritance)
Allele origin: germline
Laboratory of Genetics and Molecular Cardiology, University of São Paulo
Study: HipercolBrasil
Accession: SCV000588580.1
Submitted: (Aug 04, 2017)
Evidence details
Uncertain significance
(Sep 26, 2018)
criteria provided, single submitter
Method: clinical testing
Familial hypercholesterolemias
Allele origin: germline
Invitae
Accession: SCV000823891.2
Submitted: (Mar 28, 2019)
Evidence details
Publications
PubMed (5)
Comment:
This sequence change replaces isoleucine with threonine at codon 488 of the LDLR protein (p.Ile488Thr). The isoleucine residue is highly conserved and there is a … (more)
Pathogenic
(-)
no assertion criteria provided
Method: research
Familial hypercholesterolemia
Allele origin: germline
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum
Accession: SCV000606434.1
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
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Nykamp K Genetics in medicine : official journal of the American College of Medical Genetics 2017 PMID: 28492532
Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. Bertolini S Atherosclerosis 2013 PMID: 23375686
Mutation detection rate and spectrum in familial hypercholesterolaemia patients in the UK pilot cascade project. Taylor A Clinical genetics 2010 PMID: 20236128
The molecular basis of familial hypercholesterolemia in The Netherlands. Fouchier SW Human genetics 2001 PMID: 11810272
Clinical expression of familial hypercholesterolemia in clusters of mutations of the LDL receptor gene that cause a receptor-defective or receptor-negative phenotype. Bertolini S Arteriosclerosis, thrombosis, and vascular biology 2000 PMID: 10978268

Record last updated Oct 08, 2021