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NM_000527.5(LDLR):c.1721G>A (p.Arg574His)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely pathogenic(4);Uncertain significance(2)

Review status:
criteria provided, conflicting interpretations
Submissions:
6 (Most recent: Jan 7, 2021)
Last evaluated:
Feb 11, 2020
Accession:
VCV000251996.6
Variation ID:
251996
Description:
single nucleotide variant
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NM_000527.5(LDLR):c.1721G>A (p.Arg574His)

Allele ID
246297
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
19p13.2
Genomic location
19: 11116874 (GRCh38) GRCh38 UCSC
19: 11227550 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000019.10:g.11116874G>A
NC_000019.9:g.11227550G>A
NM_000527.5:c.1721G>A MANE Select NP_000518.1:p.Arg574His missense
... more HGVS
Protein change
R574H, R447H, R533H, R406H
Other names
-
Canonical SPDI
NC_000019.10:11116873:G:A
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
-
Links
ClinGen: CA036197
LDLR-LOVD, British Heart Foundation: LDLR_000233
UniProtKB: P01130#VAR_072852
Varsome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Likely pathogenic 2 criteria provided, multiple submitters, no conflicts Nov 11, 2019 RCV000791382.4
Likely pathogenic 1 criteria provided, single submitter Feb 11, 2020 RCV001256078.1
Conflicting interpretations of pathogenicity 3 criteria provided, conflicting interpretations Mar 25, 2016 RCV000237135.4
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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
3087 3287

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Uncertain significance
(Mar 01, 2016)
criteria provided, single submitter
Method: research
Familial hypercholesterolemia
Allele origin: germline
Laboratory of Genetics and Molecular Cardiology, University of São Paulo
Study: HipercolBrasil
Accession: SCV000588604.1
Submitted: (Aug 04, 2017)
Evidence details
Uncertain significance
(Mar 01, 2016)
criteria provided, single submitter
Method: research
Familial hypercholesterolemia
Allele origin: germline
Fundacion Hipercolesterolemia Familiar
Study: SAFEHEART
Accession: SCV000607631.1
Submitted: (Apr 20, 2017)
Evidence details
Likely pathogenic
(Oct 14, 2019)
criteria provided, single submitter
Method: clinical testing
Familial hypercholesterolemia
Allele origin: germline
Color Health, Inc
Accession: SCV001355014.1
Submitted: (May 19, 2020)
Comment:
This missense variant (also known as p.Arg553His in the mature protein) replaces arginine with histidine at codon 574 in the LDLR type B repeat 5 … (more)
Evidence details
Likely pathogenic
(Feb 11, 2020)
criteria provided, single submitter
Method: clinical testing
Hypercholesterolemia
(Autosomal dominant inheritance)
Allele origin: maternal
New York Genome Center
Study: CSER-NYCKidSeq
Accession: SCV001432865.1
Submitted: (Sep 03, 2020)
Evidence details
Publications
PubMed (3)
Comment:
The c.1721G>A, p.Arg574His variant in the LDLR gene has been observed in individuals affected with familial hypercholesterolemia [PMID: 20018285; PMID: 25461735; PMID: 23375686]. The variant … (more)
Likely pathogenic
(Nov 11, 2019)
criteria provided, single submitter
Method: clinical testing
Familial hypercholesterolemia
Allele origin: germline
Invitae
Accession: SCV000836468.4
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (6)
Comment:
This sequence change replaces arginine with histidine at codon 574 of the LDLR protein (p.Arg574His). The arginine residue is highly conserved and there is a … (more)
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: SCV000295612.2
Submitted: (Apr 20, 2016)
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
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
The genetic spectrum of familial hypercholesterolemia in south-eastern Poland. Sharifi M Metabolism: clinical and experimental 2016 PMID: 26892515
Familial hypercholesterolemia in Brazil: cascade screening program, clinical and genetic aspects. Jannes CE Atherosclerosis 2015 PMID: 25461735
Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. Bertolini S Atherosclerosis 2013 PMID: 23375686
Low-density lipoprotein receptor gene familial hypercholesterolemia variant database: update and pathological assessment. Usifo E Annals of human genetics 2012 PMID: 22881376
Pseudoxanthoma elasticum and familial hypercholesterolemia: a deleterious combination of cardiovascular risk factors. Pisciotta L Atherosclerosis 2010 PMID: 20018285
The type of LDLR gene mutation predicts cardiovascular risk in children with familial hypercholesterolemia. Guardamagna O The Journal of pediatrics 2009 PMID: 19446849
Identification of recurrent and novel mutations in the LDL receptor gene in German patients with familial hypercholesterolemia. Nauck MS Human mutation 2001 PMID: 11462246

Record last updated May 10, 2021