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NM_000527.5(LDLR):c.344G>A (p.Arg115His)

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Interpretation:
Uncertain significance​

Review status:
reviewed by expert panel FDA Recognized Database
Submissions:
10 (Most recent: Sep 27, 2021)
Last evaluated:
Jun 7, 2021
Accession:
VCV000225402.10
Variation ID:
225402
Description:
single nucleotide variant
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NM_000527.5(LDLR):c.344G>A (p.Arg115His)

Allele ID
227401
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
19p13.2
Genomic location
19: 11105250 (GRCh38) GRCh38 UCSC
19: 11215926 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NM_000527.4:c.344G>A NP_000518.1:p.Arg115His missense
NC_000019.10:g.11105250G>A
NC_000019.9:g.11215926G>A
... more HGVS
Protein change
R115H, R74H
Other names
FH Fukuoka
NM_000527.5(LDLR):c.344G>A
Canonical SPDI
NC_000019.10:11105249:G:A
Functional consequence
-
Global minor allele frequency (GMAF)
0.00020 (A)

Allele frequency
Trans-Omics for Precision Medicine (TOPMed) 0.00011
The Genome Aggregation Database (gnomAD), exomes 0.00018
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
1000 Genomes Project 0.00020
The Genome Aggregation Database (gnomAD) 0.00013
Exome Aggregation Consortium (ExAC) 0.00018
Links
ClinGen: CA043240
LDLR-LOVD, British Heart Foundation: LDLR_000052
dbSNP: rs201102461
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Uncertain significance 7 reviewed by expert panel Jun 7, 2021 RCV000237176.9
Uncertain significance 3 criteria provided, multiple submitters, no conflicts Dec 19, 2019 RCV000771221.4
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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
3091 3291

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Uncertain significance
(Jun 07, 2021)
reviewed by expert panel
Method: curation
Familial hypercholesterolemia 1
(Semidominant inheritance)
Allele origin: germline
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, ClinGen
FDA Recognized Database
Accession: SCV001960908.1
Submitted: (Sep 27, 2021)
Evidence details
Other databases
https://erepo.clinicalgenome.org…
Comment:
The NM_000527.5(LDLR):c.344G>A (p.Arg115His) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PS3) as defined by the ClinGen … (more)
Uncertain significance
(Mar 18, 2016)
criteria provided, single submitter
Method: reference population
Familial hypercholesterolemia 1
Allele origin: germline
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center
Accession: SCV000267384.1
Submitted: (Apr 14, 2016)
Evidence details
Publications
PubMed (1)
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: SCV000294641.2
Submitted: (Apr 20, 2016)
Evidence details
Publications
PubMed (4)
Likely benign
(Dec 16, 2016)
criteria provided, single submitter
Method: clinical testing
Familial hypercholesterolemia 1
Allele origin: germline
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix
Accession: SCV000503144.1
Submitted: (Jan 23, 2017)
Evidence details
Comment:
subject mutated among 2600 FH index cases screened = 1 /previously described in association with FH / Software predictions: Conflicting
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: SCV000599327.1
Submitted: (Apr 17, 2017)
Evidence details
Likely pathogenic
(May 01, 2017)
criteria provided, single submitter
Method: clinical testing
Familial hypercholesterolemia 1
Allele origin: germline
Illumina Clinical Services Laboratory,Illumina
Accession: SCV000915812.1
Submitted: (Feb 01, 2019)
Evidence details
Publications
PubMed (5)
Comment:
The LDLR c.344G>A (p.Arg115His) missense variant has been reported in five studies and is found in a total of eight individuals with hypercholesterolemia, including one … (more)
Uncertain significance
(Nov 01, 2019)
criteria provided, single submitter
Method: clinical testing
Familial hypercholesterolemia
Allele origin: germline
Invitae
Accession: SCV001225051.1
Submitted: (Feb 06, 2020)
Evidence details
Publications
PubMed (10)
Comment:
This sequence change replaces arginine with histidine at codon 115 of the LDLR protein (p.Arg115His). The arginine residue is highly conserved and there is a … (more)
Uncertain significance
(Dec 19, 2019)
criteria provided, single submitter
Method: clinical testing
Familial hypercholesterolemia
Allele origin: germline
Color Health, Inc
Accession: SCV000903315.2
Submitted: (May 19, 2020)
Comment:
This missense variant (also known as p.Arg94His in the mature protein) replaces arginine with histidine at codon 115 of the LDLR protein. Computational prediction is … (more)
Evidence details
Pathogenic
(-)
no assertion criteria provided
Method: research
Familial hypercholesterolemia
Allele origin: germline
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum
Accession: SCV000606093.1
Submitted: (Apr 25, 2017)
Evidence details
Uncertain significance
(Sep 16, 2020)
no assertion criteria provided
Method: clinical testing
Familial hypercholesterolemia
Allele origin: germline
Natera, Inc.
Accession: SCV001456140.1
Submitted: (Dec 28, 2020)
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
Detection of Familial Hypercholesterolemia Using Next Generation Sequencing in Two Population-Based Cohorts. Kim HN Chonnam medical journal 2018 PMID: 29399563
Detection of common sequence variations of familial hypercholesterolemia in Taiwan using DNA mass spectrometry. Chiou KR Journal of clinical lipidology 2017 PMID: 28502495
The UCL low-density lipoprotein receptor gene variant database: pathogenicity update. Leigh S Journal of medical genetics 2017 PMID: 27821657
Lipoprotein metabolism in familial hypercholesterolemia: Serial assessment using a one-step ultracentrifugation method. Tada H Practical laboratory medicine 2015 PMID: 28932795
Array-based resequencing for mutations causing familial hypercholesterolemia. Chiou KR Atherosclerosis 2011 PMID: 21376320
Molecular genetic epidemiology of homozygous familial hypercholesterolemia in the Hokuriku district of Japan. Mabuchi H Atherosclerosis 2011 PMID: 21146822
Detection of mutations and large rearrangements of the low-density lipoprotein receptor gene in Taiwanese patients with familial hypercholesterolemia. Chiou KR The American journal of cardiology 2010 PMID: 20538126
Update of Japanese common LDLR gene mutations and their phenotypes: Mild type mutation L547V might predominate in the Japanese population. Miyake Y Atherosclerosis 2009 PMID: 18718593
Novel and recurrent mutations of the LDL receptor gene in Korean patients with familial hypercholesterolemia. Kim JH Molecules and cells 2004 PMID: 15359125
Identification and characterization of LDL receptor gene mutations in hyperlipidemic Chinese. Chang JH Journal of lipid research 2003 PMID: 12837857
Molecular genetic analysis of familial hypercholesterolemia: spectrum and regional difference of LDL receptor gene mutations in Japanese population. Yu W Atherosclerosis 2002 PMID: 12417285
Low-density lipoprotein receptor gene mutations in a Southeast Asian population with familial hypercholesterolemia. Khoo KL Clinical genetics 2000 PMID: 11005141
LDLR Database (second edition): new additions to the database and the software, and results of the first molecular analysis. Varret M Nucleic acids research 1998 PMID: 9399845
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/42638e60-83a0-44a9-aefb-814182bee33a - - - -

Text-mined citations for rs201102461...

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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 21, 2021