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NM_000527.5(LDLR):c.1247G>A (p.Arg416Gln)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely pathogenic(3);Pathogenic(2);Uncertain significance(1)

Review status:
criteria provided, conflicting interpretations
Submissions:
8 (Most recent: Jun 11, 2021)
Last evaluated:
Sep 24, 2020
Accession:
VCV000251752.7
Variation ID:
251752
Description:
single nucleotide variant
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NM_000527.5(LDLR):c.1247G>A (p.Arg416Gln)

Allele ID
246066
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
19p13.2
Genomic location
19: 11113338 (GRCh38) GRCh38 UCSC
19: 11224014 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000019.10:g.11113338G>A
NC_000019.9:g.11224014G>A
NM_000527.5:c.1247G>A MANE Select NP_000518.1:p.Arg416Gln missense
... more HGVS
Protein change
R416Q, R248Q, R375Q, R289Q
Other names
-
Canonical SPDI
NC_000019.10:11113337:G:A
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD) 0.00003
Links
ClinGen: CA033210
LDLR-LOVD, British Heart Foundation: LDLR_000379
UniProtKB: P01130#VAR_005380
dbSNP: rs773658037
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 5 criteria provided, multiple submitters, no conflicts Jan 21, 2019 RCV000237115.5
Pathogenic 1 criteria provided, single submitter Dec 13, 2016 RCV000437123.1
Conflicting interpretations of pathogenicity 2 criteria provided, conflicting interpretations Sep 24, 2020 RCV001182458.3
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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
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: SCV000295324.2
Submitted: (Apr 20, 2016)
Evidence details
Publications
PubMed (3)
Likely pathogenic
(Mar 01, 2016)
criteria provided, single submitter
Method: research
Familial hypercholesterolemia
(Autosomal dominant inheritance)
Allele origin: germline
Fundacion Hipercolesterolemia Familiar
Study: SAFEHEART
Accession: SCV000607580.1
Submitted: (Apr 20, 2017)
Evidence details
Pathogenic
(Dec 13, 2016)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000520999.3
Submitted: (Jan 29, 2019)
Evidence details
Comment:
The R416Q variant in the LDLR gene has been reported previously in association with familial hypercholesterolemia (Thiart et al., 1998; Fouchier et al., 2001; Hollants … (more)
Uncertain significance
(Sep 17, 2019)
criteria provided, single submitter
Method: clinical testing
Familial hypercholesterolemia
Allele origin: germline
Invitae
Accession: SCV001380378.1
Submitted: (Feb 06, 2020)
Evidence details
Publications
PubMed (14)
Comment:
This sequence change replaces arginine with glutamine at codon 416 of the LDLR protein (p.Arg416Gln). The arginine residue is highly conserved and there is a … (more)
Pathogenic
(Jan 21, 2019)
criteria provided, single submitter
Method: research
Familial hypercholesterolemia 1
Allele origin: germline
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia
Accession: SCV001432622.1
Submitted: (Sep 16, 2020)
Evidence details
Likely pathogenic
(Sep 24, 2020)
criteria provided, single submitter
Method: clinical testing
Familial hypercholesterolemia
Allele origin: germline
Color Health, Inc
Accession: SCV001347902.2
Submitted: (Jun 11, 2021)
Evidence details
Comment:
This missense variant (also known as p.Arg395Gln in the mature protein) replaces arginine with glutamine at codon 416 in the LDLR type B repeat 1 … (more)
Pathogenic
(-)
no assertion criteria provided
Method: research
Familial hypercholesterolemia
Allele origin: germline
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum
Accession: SCV000606373.1
Submitted: (Apr 25, 2017)
Evidence details
Uncertain significance
(Jan 22, 2020)
no assertion criteria provided
Method: curation
Familial hypercholesterolemia 1
(Autosomal dominant inheritance)
Allele origin: germline
Broad Institute Rare Disease Group, Broad Institute
Accession: SCV001422632.1
Submitted: (Mar 09, 2020)
Evidence details
Publications
PubMed (5)
Other databases
https://erepo.clinicalgenome.org…
Comment:
The p.Arg416Gln (sometimes called p.Arg395Gln) variant in LDLR has been reported in at least 84 individuals (including 1 German, 1 Spanish, and 1 Dutch individuals) … (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
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
Spectrum of mutations in index patients with familial hypercholesterolemia in Singapore: Single center study. Pek SLT Atherosclerosis 2018 PMID: 29353225
Clinical features of bilateral temporal bone xanthoma with LDLR gene mutation. Han Y International journal of pediatric otorhinolaryngology 2015 PMID: 25921077
Functional characterization and classification of frequent low-density lipoprotein receptor variants. Etxebarria A Human mutation 2015 PMID: 25378237
Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. Bertolini S Atherosclerosis 2013 PMID: 23375686
Cardiovascular risk in relation to functionality of sequence variants in the gene coding for the low-density lipoprotein receptor: a study among 29,365 individuals tested for 64 specific low-density lipoprotein-receptor sequence variants. Huijgen R European heart journal 2012 PMID: 22390909
Microfluidic amplification as a tool for massive parallel sequencing of the familial hypercholesterolemia genes. Hollants S Clinical chemistry 2012 PMID: 22294733
Array-based resequencing for mutations causing familial hypercholesterolemia. Chiou KR Atherosclerosis 2011 PMID: 21376320
Genomic characterization of large rearrangements of the LDLR gene in Czech patients with familial hypercholesterolemia. Goldmann R BMC medical genetics 2010 PMID: 20663204
Functionality of sequence variants in the genes coding for the low-density lipoprotein receptor and apolipoprotein B in individuals with inherited hypercholesterolemia. Huijgen R Human mutation 2010 PMID: 20506408
Molecular characterization of familial hypercholesterolemia in Spain: identification of 39 novel and 77 recurrent mutations in LDLR. Mozas P Human mutation 2004 PMID: 15241806
The molecular basis of familial hypercholesterolemia in The Netherlands. Fouchier SW Human genetics 2001 PMID: 11810272
Mutations in the low-density-lipoprotein receptor gene in German patients with familial hypercholesterolaemia. Weiss N Journal of inherited metabolic disease 2000 PMID: 11196104
Mutation analysis in 46 German families with familial hypercholesterolemia: identification of 8 new mutations. Mutations in brief no. 226. Online. Ebhardt M Human mutation 1999 PMID: 10090484
Two novel and two known low-density lipoprotein receptor gene mutations in German patients with familial hypercholesterolemia. Thiart R Human mutation 1998 PMID: 9452095
Molecular genetics of familial hypercholesterolaemia in Norway. Leren TP Journal of internal medicine 1997 PMID: 9104431
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/b9f86792-abc4-44e3-9c2b-2d045358aadf - - - -

Text-mined citations for rs773658037...

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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 Aug 27, 2021