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NM_000527.5(LDLR):c.1216C>A (p.Arg406=)

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Interpretation:
Pathogenic/Likely pathogenic​

Review status:
criteria provided, multiple submitters, no conflicts
Submissions:
10 (Most recent: May 26, 2021)
Last evaluated:
May 24, 2021
Accession:
VCV000003746.6
Variation ID:
3746
Description:
single nucleotide variant
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NM_000527.5(LDLR):c.1216C>A (p.Arg406=)

Allele ID
18785
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
19p13.2
Genomic location
19: 11113307 (GRCh38) GRCh38 UCSC
19: 11223983 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000019.10:g.11113307C>A
NC_000019.9:g.11223983C>A
NM_000527.5:c.1216C>A MANE Select NP_000518.1:p.Arg406= synonymous
... more HGVS
Protein change
-
Other names
R385R
NP_000518.1:p.Arg406Arg=
Canonical SPDI
NC_000019.10:11113306:C:A
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
-
Links
ClinGen: CA023436
LDLR-LOVD, British Heart Foundation: LDLR_000813
OMIM: 606945.0065
dbSNP: rs121908043
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 8 criteria provided, multiple submitters, no conflicts May 24, 2021 RCV000003944.11
Pathogenic 2 criteria provided, multiple submitters, no conflicts Mar 19, 2018 RCV000588218.2
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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
3087 3287

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Pathogenic
(Apr 13, 2018)
criteria provided, single submitter
Method: clinical testing
Familial hypercholesterolemia
Allele origin: germline
Invitae
Accession: SCV000833922.1
Submitted: (Aug 29, 2018)
Evidence details
Publications
PubMed (6)
Comment:
This sequence change affects codon 406 of the LDLR mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid … (more)
Likely pathogenic
(Mar 03, 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: SCV001432549.1
Submitted: (Sep 16, 2020)
Evidence details
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: SCV000295305.2
Submitted: (Apr 20, 2016)
Evidence details
Publications
PubMed (3)
Pathogenic
(Mar 01, 2016)
criteria provided, single submitter
Method: curation, literature only
Familial hypercholesterolemia
(Autosomal dominant inheritance)
Allele origin: germline, not applicable
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge
Accession: SCV000599368.1
Submitted: (Apr 17, 2017)
Evidence details
Pathogenic
(Jul 10, 2017)
criteria provided, single submitter
Method: clinical testing
Familial hypercholesterolemia
Allele origin: germline
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697190.1
Submitted: (Jan 25, 2018)
Evidence details
Publications
PubMed (9)
Comment:
Variant summary: The LDLR c.1216C>A (p.Arg406Arg) variant involves the alteration of a conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a … (more)
Pathogenic
(Mar 19, 2018)
criteria provided, single submitter
Method: clinical testing
Familial hypercholesterolemia
Allele origin: germline
Color Health, Inc
Accession: SCV001349490.1
Submitted: (May 19, 2020)
Comment:
This variant changes a single nucleotide in exon 9 (c.1216C>A) of the LDLR gene and has been shown to create a new splice acceptor site. … (more)
Evidence details
Pathogenic
(Dec 30, 2019)
criteria provided, single submitter
Method: clinical testing
Familial hypercholesterolemia 1
Allele origin: germline
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute
Accession: SCV001433518.1
Submitted: (Jul 24, 2020)
Evidence details
Pathogenic
(May 24, 2021)
criteria provided, single submitter
Method: clinical testing
Familial hypercholesterolemia 1
Allele origin: germline
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II
Accession: SCV001653629.1
Submitted: (May 26, 2021)
Evidence details
Publications
PubMed (4)
Comment:
altered splicing
Pathogenic
(-)
no assertion criteria provided
Method: research
Familial hypercholesterolemia
Allele origin: germline
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum
Accession: SCV000606361.1
Submitted: (Apr 25, 2017)
Evidence details
Pathogenic
(Jun 01, 2008)
no assertion criteria provided
Method: literature only
HYPERCHOLESTEROLEMIA, FAMILIAL, 1
Allele origin: germline
OMIM
Accession: SCV000024109.3
Submitted: (Dec 30, 2010)
Evidence details
Publications
PubMed (2)

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
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
Mutation detection in Chinese patients with familial hypercholesterolemia. Du R SpringerPlus 2016 PMID: 28028493
Familial hypercholesterolemia mutations in the Middle Eastern and North African region: a need for a national registry. Bamimore MA Journal of clinical lipidology 2015 PMID: 25911074
Novel mutations of low-density lipoprotein receptor gene in China patients with familial hypercholesterolemia. Fan LL Applied biochemistry and biotechnology 2015 PMID: 25846081
Low-density lipoprotein receptor gene familial hypercholesterolemia variant database: update and pathological assessment. Usifo E Annals of human genetics 2012 PMID: 22881376
Molecular basis of autosomal dominant hypercholesterolemia: assessment in a large cohort of hypercholesterolemic children. van der Graaf A Circulation 2011 PMID: 21382890
Altered mRNA splicing in lipoprotein disorders. Calandra S Current opinion in lipidology 2011 PMID: 21157333
Molecular spectrum of autosomal dominant hypercholesterolemia in France. Marduel M Human mutation 2010 PMID: 20809525
Functional analysis of the synonymous R385R mutation in the low-density lipoprotein receptor gene. Tveten K Genetic testing and molecular biomarkers 2009 PMID: 19371225
Silent exonic mutations in the low-density lipoprotein receptor gene that cause familial hypercholesterolemia by affecting mRNA splicing. Defesche JC Clinical genetics 2008 PMID: 18400033
A rare polymorphism in the low density lipoprotein (LDL) gene that affects mRNA splicing. Bourbon M Atherosclerosis 2007 PMID: 17335829
Genetic defects causing familial hypercholesterolaemia: identification of deletions and duplications in the LDL-receptor gene and summary of all mutations found in patients attending the Hammersmith Hospital Lipid Clinic. Tosi I Atherosclerosis 2007 PMID: 17094996

Text-mined citations for rs121908043...

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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