ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.691T>G (p.Cys231Gly)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000527.5(LDLR):c.691T>G (p.Cys231Gly)
Variation ID: 251397 Accession: VCV000251397.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11105597 (GRCh38) [ NCBI UCSC ] 19: 11216273 (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 Oct 15, 2016 May 1, 2024 Mar 27, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000527.5:c.691T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Cys231Gly missense NM_001195798.2:c.691T>G NP_001182727.1:p.Cys231Gly missense NM_001195799.2:c.568T>G NP_001182728.1:p.Cys190Gly missense NM_001195800.2:c.314-1795T>G intron variant NM_001195803.2:c.314-968T>G intron variant NC_000019.10:g.11105597T>G NC_000019.9:g.11216273T>G NG_009060.1:g.21217T>G LRG_274:g.21217T>G LRG_274t1:c.691T>G LRG_274p1:p.Cys231Gly P01130:p.Cys231Gly - Protein change
- C231G, C190G
- Other names
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- Canonical SPDI
- NC_000019.10:11105596:T:G
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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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
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 |
4073 | 4349 |
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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Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Nov 5, 2016 | RCV000237108.6 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 27, 2023 | RCV001857824.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 23, 2017 | RCV002374396.2 |
Submissions - Germline
Classification
Help
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: SCV000294911.2
First in ClinVar: Jul 29, 2016 Last updated: May 30, 2018 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 1
Observation 3:
Number of individuals with the variant: 1
Observation 4:
Number of individuals with the variant: 1
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Likely pathogenic
(Mar 01, 2016)
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criteria provided, single submitter
Method: research
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Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge
Accession: SCV000322912.1
First in ClinVar: Oct 15, 2016 Last updated: Oct 15, 2016 |
Comment:
0/190 non-FH alleles
Observation 1:
Comment on evidence:
%MAF (ExAC):0.0008716
Observation 2: |
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Likely pathogenic
(Nov 05, 2016)
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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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Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation
Additional submitter:
Centre of Molecular Biology and Gene Therapy, University Hospital Brno
Accession: SCV000540755.1
First in ClinVar: Oct 15, 2016 Last updated: Oct 15, 2016 |
Comment:
Disrupt disulfide bridge between Cys216 and Cys231.
Number of individuals with the variant: 1
Clinical Features:
Hypercholesterolemia (present)
Age: 40-49 years
Sex: female
Ethnicity/Population group: Caucasian
Geographic origin: Czech Republic
Tissue: Whole blood
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Likely pathogenic
(Feb 01, 2013)
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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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Arcensus
Accession: SCV002564613.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
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Pathogenic
(Mar 27, 2023)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003922713.1
First in ClinVar: May 13, 2023 Last updated: May 13, 2023 |
Comment:
Variant summary: LDLR c.691T>G (p.Cys231Gly) results in a non-conservative amino acid change located in the fifth class A repeat (IPR002172) of the encoded protein sequence. … (more)
Variant summary: LDLR c.691T>G (p.Cys231Gly) results in a non-conservative amino acid change located in the fifth class A repeat (IPR002172) of the encoded protein sequence. The class A repeats form the binding sites for LDL and contain six cysteine residues involved in disulfide bond formation that are required for structural integrity (InterPro). Numerous missense changes affecting cysteine residues within LDLR class A repeats are found among patients with hypercholesterolemia (HGMD), in addition, other variants affecting the same residue (Cys231), have been reported in affected individuals (HGMD). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 246490 control chromosomes (gnomAD). The variant, c.691T>G (aka. C210G), has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (e.g. Heath_2001, Tichy_2012, Leren_2021), and was described as a frequent founder variant in Norwegian FH patients (Leren_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic (n=2) / likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Sep 26, 2021)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002149411.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys231 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.Cys231 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 10422804, 10782930, 19073363), 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: 251397). This variant is also known as C210G. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 10422804, 11313767, 22698793). This variant is present in population databases (rs746091400, ExAC 0.01%). This sequence change replaces cysteine with glycine at codon 231 of the LDLR protein (p.Cys231Gly). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and glycine. (less)
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Pathogenic
(Oct 23, 2017)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002668203.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.C231G pathogenic mutation (also known as c.691T>G), located in coding exon 4 of the LDLR gene, results from a T to G substitution at … (more)
The p.C231G pathogenic mutation (also known as c.691T>G), located in coding exon 4 of the LDLR gene, results from a T to G substitution at nucleotide position 691. The cysteine at codon 231 is replaced by glycine, an amino acid with highly dissimilar properties. This alteration is located in the ligand binding domain, and is expected to disrupt a disulfide bond. This alteration, also referred to as C210G, has been reported in multiple individuals with familial hypercholesterolemia (FH), and has been reported as commonly occurring in Norwegian FH cohorts (Sundvold H et al. Hum Mutat. 1996;7:70-1; Heath KE et al. Eur J Hum Genet. 2001;9:244-52; Dušková L et al. Atherosclerosis. 2011;216:139-45; Tichý L et al. Atherosclerosis. 2012;223(2):401-8). In addition, other alterations affecting this amino acid (C231Y, C231R, and C231W) have also been reported in association with FH (Shin JA et al. Clin Genet. 2000;57(3):225-9; Wang L et al. Nutr Metab Cardiovasc Dis. 2009;19(6):391-400; Marduel M et al. Hum Mutat. 2010;31(11):E1811-24). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
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Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum
Accession: SCV000606205.1
First in ClinVar: Oct 15, 2016 Last updated: Oct 15, 2016 |
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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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Molecular genetic testing for autosomal dominant hypercholesterolemia in 29,449 Norwegian index patients and 14,230 relatives during the years 1993-2020. | Leren TP | Atherosclerosis | 2021 | PMID: 33740630 |
The molecular basis of familial hypercholesterolemia in the Czech Republic: spectrum of LDLR mutations and genotype-phenotype correlations. | Tichý L | Atherosclerosis | 2012 | PMID: 22698793 |
Serum levels of proprotein convertase subtilisin/kexin type 9 in subjects with familial hypercholesterolemia indicate that proprotein convertase subtilisin/kexin type 9 is cleared from plasma by low-density lipoprotein receptor-independent pathways. | Cameron J | Translational research : the journal of laboratory and clinical medicine | 2012 | PMID: 22683370 |
An APEX-based genotyping microarray for the screening of 168 mutations associated with familial hypercholesterolemia. | Dušková L | Atherosclerosis | 2011 | PMID: 21310417 |
Molecular spectrum of autosomal dominant hypercholesterolemia in France. | Marduel M | Human mutation | 2010 | PMID: 20809525 |
Mutations in the LDL receptor gene in four Chinese homozygous familial hypercholesterolemia phenotype patients. | Wang L | Nutrition, metabolism, and cardiovascular diseases : NMCD | 2009 | PMID: 19073363 |
Update and analysis of the University College London low density lipoprotein receptor familial hypercholesterolemia database. | Leigh SE | Annals of human genetics | 2008 | PMID: 18325082 |
Missense mutations in the PCSK9 gene are associated with hypocholesterolemia and possibly increased response to statin therapy. | Berge KE | Arteriosclerosis, thrombosis, and vascular biology | 2006 | PMID: 16424354 |
A molecular genetic service for diagnosing individuals with familial hypercholesterolaemia (FH) in the United Kingdom. | Heath KE | European journal of human genetics : EJHG | 2001 | PMID: 11313767 |
Identification of four novel mutations of the low-density lipoprotein receptor gene in Korean patients with familial hypercholesterolemia. | Shin JA | Clinical genetics | 2000 | PMID: 10782930 |
Founder mutations in the LDL receptor gene contribute significantly to the familial hypercholesterolemia phenotype in the indigenous South African population of mixed ancestry. | Loubser O | Clinical genetics | 1999 | PMID: 10422804 |
Mutant transcripts of the LDL receptor gene: mRNA structure and quantity. | Rødningen OK | Human mutation | 1999 | PMID: 10090473 |
A common missense mutation (C210G) in the LDL receptor gene among Norwegian familial hypercholesterolemia subjects. | Sundvold H | Human mutation | 1996 | PMID: 8664907 |
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 |
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Text-mined citations for rs746091400 ...
HelpRecord last updated Sep 29, 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.