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NM_000527.5(LDLR):c.2242G>A (p.Asp748Asn)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely benign(1);Uncertain significance(4)

Review status:
criteria provided, conflicting interpretations
Submissions:
7 (Most recent: Jan 7, 2021)
Last evaluated:
Aug 20, 2020
Accession:
VCV000183133.7
Variation ID:
183133
Description:
single nucleotide variant
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NM_000527.5(LDLR):c.2242G>A (p.Asp748Asn)

Allele ID
181275
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
19p13.2
Genomic location
19: 11123275 (GRCh38) GRCh38 UCSC
19: 11233951 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000019.10:g.11123275G>A
NC_000019.9:g.11233951G>A
NG_009060.1:g.38895G>A
... more HGVS
Protein change
D748N, D570N, D707N, D580N
Other names
NP_000518.1:p.D748N
Canonical SPDI
NC_000019.10:11123274:G:A
Functional consequence
unknown functional consequence
unclear [submitted by Dept. of Genetics and Pharmacogenomics, Merck Research Labs]
Global minor allele frequency (GMAF)
0.00020 (A)

Allele frequency
Trans-Omics for Precision Medicine (TOPMed) 0.00002
1000 Genomes Project 0.00020
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Exome Aggregation Consortium (ExAC) 0.00012
Links
ClinGen: CA023653
LDLR-LOVD, British Heart Foundation: LDLR_000290
dbSNP: rs150104358
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Uncertain significance 2 criteria provided, multiple submitters, no conflicts Aug 20, 2020 RCV001178125.2
Conflicting interpretations of pathogenicity 4 criteria provided, conflicting interpretations Aug 22, 2019 RCV000237615.6
not provided 1 no assertion provided - RCV000162012.2
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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

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Likely benign
(Mar 25, 2016)
criteria provided, single submitter
Method: literature only
Familial hypercholesterolemia
Allele origin: germline
LDLR-LOVD, British Heart Foundation
Accession: SCV000295925.2
Submitted: (Apr 20, 2016)
Evidence details
Publications
PubMed (1)
Uncertain significance
(Aug 22, 2019)
criteria provided, single submitter
Method: clinical testing
Familial hypercholesterolemia 1
(Autosomal dominant inheritance)
Allele origin: germline
Robarts Research Institute,Western University
Accession: SCV000484755.2
Submitted: (Aug 22, 2019)
Evidence details
Publications
PubMed (1)
Uncertain significance
(Jan 13, 2018)
criteria provided, single submitter
Method: clinical testing
Familial hypercholesterolemia 1
Allele origin: germline
Illumina Clinical Services Laboratory,Illumina
Accession: SCV000410544.3
Submitted: (Feb 20, 2020)
Evidence details
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
Uncertain significance
(Nov 15, 2019)
criteria provided, single submitter
Method: clinical testing
Familial hypercholesterolemia
Allele origin: germline
Color Health, Inc
Accession: SCV001342485.1
Submitted: (May 19, 2020)
Comment:
This missense variant (also known as p.Asp727Asn in the mature protein) replaces aspartic acid with asparagine at codon 748 of the LDLR protein. Computational prediction … (more)
Evidence details
Uncertain significance
(Aug 20, 2020)
criteria provided, single submitter
Method: clinical testing
Familial hypercholesterolemia
Allele origin: germline
Invitae
Accession: SCV001531711.1
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (4)
Comment:
This sequence change replaces aspartic acid with asparagine at codon 748 of the LDLR protein (p.Asp748Asn). The aspartic acid residue is weakly conserved and there … (more)
Pathogenic
(-)
no assertion criteria provided
Method: research
Familial hypercholesterolemia
Allele origin: germline
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum
Accession: SCV000606618.1
Submitted: (Apr 25, 2017)
Evidence details
not provided
(-)
no assertion provided
()
Method: in vitro
not provided
Allele origin: not applicable
Dept. of Genetics and Pharmacogenomics, Merck Research Labs
Additional submitter:
Runz lab, Institute of Human Genetics, Heidelberg
Accession: SCV000189588.1
Submitted: (Oct 06, 2014)
Comment:
In vitro functional profiling of LDL-receptor missense alleles identified through large-scale association testing
Evidence details
Publications
PubMed (1)

Functional evidence

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Functional consequence Method Result Submitter Supporting information
unknown functional consequence
  1. Method not provided
  1. Result not provided
Dept. of Genetics and Pharmacogenomics, Merck Research Labs
Additional submitter:
Runz lab, Institute of Human Genetics, Heidelberg
Accession: SCV000189588.1
Submitted: (Oct 06, 2014)
Evidence details
Publications
PubMed (1)
Comment:
unclear

Citations for this variant

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Title Author Journal Year Link
Pathogenic variant burden in the ExAC database: an empirical approach to evaluating population data for clinical variant interpretation. Kobayashi Y Genome medicine 2017 PMID: 28166811
Polygenic Versus Monogenic Causes of Hypercholesterolemia Ascertained Clinically. Wang J Arteriosclerosis, thrombosis, and vascular biology 2016 PMID: 27765764
Systematic cell-based phenotyping of missense alleles empowers rare variant association studies: a case for LDLR and myocardial infarction. Thormaehlen AS PLoS genetics 2015 PMID: 25647241
Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Do R Nature 2015 PMID: 25487149
Low-density lipoprotein receptor gene familial hypercholesterolemia variant database: update and pathological assessment. Usifo E Annals of human genetics 2012 PMID: 22881376

Text-mined citations for rs150104358...

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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 Oct 08, 2021