ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.826T>C (p.Cys276Arg)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic(2); Likely pathogenic(3); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000527.5(LDLR):c.826T>C (p.Cys276Arg)
Variation ID: 251479 Accession: VCV000251479.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11107400 (GRCh38) [ NCBI UCSC ] 19: 11218076 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jul 29, 2016 Apr 15, 2024 Mar 13, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000527.5:c.826T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Cys276Arg missense NM_001195798.2:c.826T>C NP_001182727.1:p.Cys276Arg missense NM_001195799.2:c.703T>C NP_001182728.1:p.Cys235Arg missense NM_001195800.2:c.322T>C NP_001182729.1:p.Cys108Arg missense NM_001195803.2:c.445T>C NP_001182732.1:p.Cys149Arg missense NC_000019.10:g.11107400T>C NC_000019.9:g.11218076T>C NG_009060.1:g.23020T>C LRG_274:g.23020T>C LRG_274t1:c.826T>C LRG_274p1:p.Cys276Arg P01130:p.Cys276Arg - Protein change
- C276R, C149R, C235R, C108R
- Other names
- FH Ceva
- Canonical SPDI
- NC_000019.10:11107399:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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LDLR | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3998 | 4269 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Mar 13, 2024 | RCV000238233.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 10, 2017 | RCV000781499.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 4, 2022 | RCV001384762.6 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 17, 2023 | RCV003441823.1 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Mar 25, 2016)
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criteria provided, single submitter
Method: literature only
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Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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LDLR-LOVD, British Heart Foundation
Accession: SCV000295001.2
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Number of individuals with the variant: 1
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Likely pathogenic
(Dec 16, 2016)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
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Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix
Accession: SCV000503241.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Comment:
subjects mutated among 2600 FH index cases screened = 2 / FH-Ceva / Software predictions: Damaging
Number of individuals with the variant: 2
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Uncertain significance
(Nov 10, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919579.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: The LDLR c.826T>C (p.Cys276Arg) variant involves the alteration of a conserved nucleotide that results in the alteration of a cysteine residue at the … (more)
Variant summary: The LDLR c.826T>C (p.Cys276Arg) variant involves the alteration of a conserved nucleotide that results in the alteration of a cysteine residue at the protein level that is highly conserved across species (Bertolini 2013). The variant is located in the ligand-binding domain of the LDL receptor (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index), however these predictions have not been evaluated for functional impact by in vivo/vitro studies. This variant is absent in 246246 control chromosomes (gnomAD). The variant has been reported in individuals presented with hypercholesterolemia in heterozygous form (Bertolini 2003), however without providing clear evidence for causality. One clinical diagnostic laboratoy and a databases classified this variant as likely pathogenic, without evidence for independent evaluation. Variants involving the same codon such as C276G, C276F, C276W, and C276Y have been reported in affected individuals suggesting the functional importance of this codon. Taken together, this variant is classified as VUS-possibly pathogenic, until additional evidence becomes available. (less)
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Pathogenic
(Feb 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001584407.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys276 amino acid residue in LDLR. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys276 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 10634824, 26361156), which suggests that this may be a clinically significant amino acid residue. This variant affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 251479). This variant is also known as C255R. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 10978268). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 276 of the LDLR protein (p.Cys276Arg). (less)
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Likely pathogenic
(May 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV004170055.1
First in ClinVar: Nov 25, 2023 Last updated: Nov 25, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.C255R; This variant is associated with the following publications: (PMID: 30710474, 23375686, 10978268) (less)
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Pathogenic
(Mar 13, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004812117.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
Criteria applied: PM5_STR,PS4_MOD,PM1,PM3,PM2_SUP,PP3
Clinical Features:
Hypercholesterolemia (present)
Sex: female
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Germline Functional Evidence
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 germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Systematic analysis of variants related to familial hypercholesterolemia in families with premature myocardial infarction. | Brænne I | European journal of human genetics : EJHG | 2016 | PMID: 26036859 |
Universal Screening for Familial Hypercholesterolemia in Children. | Klančar G | Journal of the American College of Cardiology | 2015 | PMID: 26361156 |
Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. | Bertolini S | Atherosclerosis | 2013 | PMID: 23375686 |
Update and analysis of the University College London low density lipoprotein receptor familial hypercholesterolemia database. | Leigh SE | Annals of human genetics | 2008 | PMID: 18325082 |
Clinical expression of familial hypercholesterolemia in clusters of mutations of the LDL receptor gene that cause a receptor-defective or receptor-negative phenotype. | Bertolini S | Arteriosclerosis, thrombosis, and vascular biology | 2000 | PMID: 10978268 |
Influence of beta(0)-thalassemia on the phenotypic expression of heterozygous familial hypercholesterolemia : a study of patients with familial hypercholesterolemia from Sardinia. | Deiana L | Arteriosclerosis, thrombosis, and vascular biology | 2000 | PMID: 10634824 |
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 rs879254692 ...
HelpRecord last updated Apr 15, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.