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NM_000527.5(LDLR):c.782G>T (p.Cys261Phe)

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Interpretation:
Pathogenic/Likely pathogenic​

Review status:
criteria provided, multiple submitters, no conflicts
Submissions:
8 (Most recent: Jan 7, 2021)
Last evaluated:
Mar 14, 2020
Accession:
VCV000003740.6
Variation ID:
3740
Description:
single nucleotide variant
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NM_000527.5(LDLR):c.782G>T (p.Cys261Phe)

Allele ID
18779
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
19p13.2
Genomic location
19: 11106652 (GRCh38) GRCh38 UCSC
19: 11217328 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000019.10:g.11106652G>T
NC_000019.9:g.11217328G>T
NM_000527.5:c.782G>T MANE Select NP_000518.1:p.Cys261Phe missense
... more HGVS
Protein change
C261F, C220F, C134F
Other names
C240F
Canonical SPDI
NC_000019.10:11106651:G:T
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
Links
ClinGen: CA023761
LDLR-LOVD, British Heart Foundation: LDLR_000647
UniProtKB: P01130#VAR_013953
OMIM: 606945.0059
dbSNP: rs121908040
Varsome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Likely pathogenic 4 criteria provided, multiple submitters, no conflicts Apr 12, 2017 RCV000003938.6
Pathogenic/Likely pathogenic 2 criteria provided, multiple submitters, no conflicts Mar 14, 2020 RCV000776469.3
Likely pathogenic 1 criteria provided, single submitter Feb 13, 2018 RCV000825593.1
Likely pathogenic 1 no assertion criteria provided Jun 1, 2014 RCV000148568.1
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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 01, 2016)
criteria provided, single submitter
Method: research
Familial hypercholesterolemia
(Autosomal dominant inheritance)
Allele origin: germline
Fundacion Hipercolesterolemia Familiar
Study: SAFEHEART
Accession: SCV000607500.1
Submitted: (Apr 20, 2017)
Evidence details
Likely pathogenic
(Feb 13, 2018)
criteria provided, single submitter
Method: clinical testing
Familial hypercholesterolemia - homozygous
(Autosomal dominant inheritance)
Allele origin: germline
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine
Accession: SCV000966935.1
Submitted: (Mar 21, 2019)
Evidence details
Publications
PubMed (5)
Comment:
The p.Cys261Phe variant in LDLR (also described as p.Cys240Phe in the literature ), has been reported in at least 5 individuals with familial hypercholesterolemi a … (more)
Likely pathogenic
(Mar 22, 2019)
criteria provided, single submitter
Method: clinical testing
Familial hypercholesterolemia
Allele origin: germline
Color Health, Inc
Accession: SCV000912019.2
Submitted: (May 19, 2020)
Comment:
This missense variant (also known as p.Cys240Phe in the mature protein) is located in the sixth LDLR type A repeat of the ligand binding domain … (more)
Evidence details
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: SCV000294970.2
Submitted: (Apr 20, 2016)
Evidence details
Publications
PubMed (3)
Likely pathogenic
(Apr 12, 2017)
criteria provided, single submitter
Method: clinical testing
Familial hypercholesterolemia 1
Allele origin: germline
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV000839987.1
Submitted: (Jun 14, 2018)
Evidence details
Comment:
This c.782G>T (p.Cys261Phe) variant has previously been detected in several patients with familial hypercholesterolemia [legacy: 240 in PMID 9767373, 16542394]. The variant was also detected … (more)
Pathogenic
(Mar 14, 2020)
criteria provided, single submitter
Method: clinical testing
Familial hypercholesterolemia
Allele origin: germline
Invitae
Accession: SCV001580704.1
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (8)
Comment:
This sequence change replaces cysteine with phenylalanine at codon 261 of the LDLR protein (p.Cys261Phe). The cysteine residue is highly conserved and there is a … (more)
Likely pathogenic
(Jun 01, 2014)
no assertion criteria provided
Method: research
Hypercholesterolaemia
(Autosomal dominant inheritance)
Allele origin: germline
CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190281.1
Submitted: (Aug 28, 2014)
Comment:
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
Evidence details
Pathogenic
(May 01, 1999)
no assertion criteria provided
Method: literature only
HYPERCHOLESTEROLEMIA, FAMILIAL, 1
Allele origin: germline
OMIM
Accession: SCV000024103.2
Submitted: (Dec 30, 2010)
Evidence details
Publications
PubMed (1)

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
Actionable exomic incidental findings in 6503 participants: challenges of variant classification. Amendola LM Genome research 2015 PMID: 25637381
[The spectrum of mutations in the low-density lipoprotein receptor gene in the Russian population]. Voevoda MI Genetika 2008 PMID: 19062533
Update and analysis of the University College London low density lipoprotein receptor familial hypercholesterolemia database. Leigh SE Annals of human genetics 2008 PMID: 18325082
Molecular genetic analysis of 1053 Danish individuals with clinical signs of familial hypercholesterolemia. Brusgaard K Clinical genetics 2006 PMID: 16542394
Application of molecular genetics for diagnosing familial hypercholesterolemia in Norway: results from a family-based screening program. Leren TP Seminars in vascular medicine 2004 PMID: 15199436
An individual with a healthy phenotype in spite of a pathogenic LDL receptor mutation (C240F). Ekström U Clinical genetics 1999 PMID: 10422803
Mutations in the low-density lipoprotein receptor gene in Swedish familial hypercholesterolaemia patients: clinical expression and treatment response. Ekström U European journal of clinical investigation 1998 PMID: 9767373
Three-dimensional structure of a cysteine-rich repeat from the low-density lipoprotein receptor. Daly NL Proceedings of the National Academy of Sciences of the United States of America 1995 PMID: 7603991
Disulfide bridges of a cysteine-rich repeat of the LDL receptor ligand-binding domain. Bieri S Biochemistry 1995 PMID: 7548065
Structures and functions of multiligand lipoprotein receptors: macrophage scavenger receptors and LDL receptor-related protein (LRP). Krieger M Annual review of biochemistry 1994 PMID: 7979249

Text-mined citations for rs121908040...

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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 Jul 07, 2021