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NM_000527.5(LDLR):c.1720C>T (p.Arg574Cys)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely pathogenic(4);Pathogenic(1);Uncertain significance(2)

Review status:
criteria provided, conflicting interpretations
Submissions:
10 (Most recent: Jul 4, 2021)
Last evaluated:
May 24, 2021
Accession:
VCV000183123.15
Variation ID:
183123
Description:
single nucleotide variant
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NM_000527.5(LDLR):c.1720C>T (p.Arg574Cys)

Allele ID
181265
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
19p13.2
Genomic location
19: 11116873 (GRCh38) GRCh38 UCSC
19: 11227549 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000019.10:g.11116873C>T
NC_000019.9:g.11227549C>T
NG_009060.1:g.32493C>T
... more HGVS
Protein change
R574C, R447C, R533C, R406C
Other names
-
Canonical SPDI
NC_000019.10:11116872:C:T
Functional consequence
no known functional consequence
non-disruptive missense [submitted by Dept. of Genetics and Pharmacogenomics, Merck Research Labs]
Global minor allele frequency (GMAF)
0.00040 (T)

Allele frequency
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00003
The Genome Aggregation Database (gnomAD) 0.00006
Exome Aggregation Consortium (ExAC) 0.00002
1000 Genomes Project 0.00040
Links
ClinGen: CA023561
LDLR-LOVD, British Heart Foundation: LDLR_000232
UniProtKB: P01130#VAR_072851
dbSNP: rs185098634
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 2 criteria provided, multiple submitters, no conflicts Oct 20, 2020 RCV000791378.4
Likely pathogenic 2 criteria provided, single submitter Oct 1, 2018 RCV000161998.7
Conflicting interpretations of pathogenicity 6 criteria provided, conflicting interpretations May 24, 2021 RCV000238063.5
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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
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: SCV000295611.2
Submitted: (Apr 20, 2016)
Evidence details
Publications
PubMed (5)
Uncertain significance
(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: SCV000503397.1
Submitted: (Jan 23, 2017)
Evidence details
Comment:
subject mutated among 2600 FH index cases screened = 1, family member=1 /FH-Germany/software prediction damaging
Uncertain significance
(Mar 01, 2016)
criteria provided, single submitter
Method: research
Familial hypercholesterolemia
Allele origin: germline
Fundacion Hipercolesterolemia Familiar
Study: SAFEHEART
Accession: SCV000607630.1
Submitted: (Apr 20, 2017)
Evidence details
Likely pathogenic
(Jan 02, 2019)
criteria provided, single submitter
Method: clinical testing
Familial hypercholesterolemia
Allele origin: germline
Color Health, Inc
Accession: SCV001349170.1
Submitted: (May 19, 2020)
Comment:
This missense variant (also known as p.Arg553Cys in the mature protein) is located in the LDLR type B repeat 5 of the EGF precursor homology … (more)
Evidence details
Pathogenic
(Oct 20, 2020)
criteria provided, single submitter
Method: clinical testing
Familial hypercholesterolemia
Allele origin: germline
Invitae
Accession: SCV000752408.4
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (9)
Comment:
This sequence change replaces arginine with cysteine at codon 574 of the LDLR protein (p.Arg574Cys). The arginine residue is highly conserved and there is a … (more)
Likely 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: SCV001653648.1
Submitted: (May 26, 2021)
Evidence details
Publications
PubMed (8)
Likely pathogenic
(Oct 01, 2018)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
CeGaT Praxis fuer Humangenetik Tuebingen
Accession: SCV001151665.7
Submitted: (Jul 04, 2021)
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: SCV000606498.1
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: SCV001423052.1
Submitted: (Mar 09, 2020)
Evidence details
Publications
PubMed (9)
Other databases
https://erepo.clinicalgenome.org…
Comment:
The p.Arg574Cys variant in LDLR has been reported in 14 individuals with familial hypercholesterolemia (PMID: 29290422, 25647241, 22698793, 20145306, 25487149, 23375686, 11462246, 26892515, 19446849), and … (more)
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: SCV000189573.1
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
no known 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: SCV000189573.1
Submitted: (Oct 06, 2014)
Evidence details
Publications
PubMed (1)
Comment:
non-disruptive missense

Citations for this variant

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Title Author Journal Year Link
Homozygous familial hypercholesterolemia in Italy: Clinical and molecular features. Bertolini S Atherosclerosis 2020 PMID: 32977124
Population genetic screening efficiently identifies carriers of autosomal dominant diseases. Grzymski JJ Nature medicine 2020 PMID: 32719484
Lipid profile and genetic status in a familial hypercholesterolemia pediatric population: exploring the LDL/HDL ratio. Di Taranto MD Clinical chemistry and laboratory medicine 2019 PMID: 30710474
Short-term effect of rosuvastatin treatment on arterial stiffness in individuals with newly-diagnosed heterozygous familial hypercholesterolemia. Canepa M International journal of cardiology 2018 PMID: 29290422
Mutation detection in Chinese patients with familial hypercholesterolemia. Du R SpringerPlus 2016 PMID: 28028493
The genetic spectrum of familial hypercholesterolemia in south-eastern Poland. Sharifi M Metabolism: clinical and experimental 2016 PMID: 26892515
Identification of Medically Actionable Secondary Findings in the 1000 Genomes. Olfson E PloS one 2015 PMID: 26332594
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
Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. Bertolini S Atherosclerosis 2013 PMID: 23375686
The molecular basis of familial hypercholesterolemia in the Czech Republic: spectrum of LDLR mutations and genotype-phenotype correlations. Tichý L Atherosclerosis 2012 PMID: 22698793
Molecular characterization of Polish patients with familial hypercholesterolemia: novel and recurrent LDLR mutations. Chmara M Journal of applied genetics 2010 PMID: 20145306
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
Genetic diagnosis of familial hypercholesterolemia using a DNA-array based platform. Alonso R Clinical biochemistry 2009 PMID: 19318025
The relationship of molecular genetic to clinical diagnosis of familial hypercholesterolemia in a Danish population. Damgaard D Atherosclerosis 2005 PMID: 15823288
Identification of recurrent and novel mutations in the LDL receptor gene in German patients with familial hypercholesterolemia. Nauck MS Human mutation 2001 PMID: 11462246
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/9886bec9-e3bc-432e-99b4-59c566aa0c6d - - - -

Text-mined citations for rs185098634...

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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