ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.81C>G (p.Cys27Trp)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000527.5(LDLR):c.81C>G (p.Cys27Trp)
Variation ID: 226304 Accession: VCV000226304.52
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11100236 (GRCh38) [ NCBI UCSC ] 19: 11210912 (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 May 22, 2016 Aug 4, 2024 May 6, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000527.5:c.81C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Cys27Trp missense NM_000527.4(LDLR):c.81C>G NM_001195798.2:c.81C>G NP_001182727.1:p.Cys27Trp missense NM_001195799.2:c.81C>G NP_001182728.1:p.Cys27Trp missense NM_001195800.2:c.81C>G NP_001182729.1:p.Cys27Trp missense NM_001195803.2:c.81C>G NP_001182732.1:p.Cys27Trp missense NC_000019.10:g.11100236C>G NC_000019.9:g.11210912C>G NG_009060.1:g.15856C>G LRG_274:g.15856C>G LRG_274t1:c.81C>G LRG_274p1:p.Cys27Trp P01130:p.Cys27Trp - Protein change
- C27W
- Other names
- NP_000518.1:p.C27W
- NM_000527.5(LDLR):c.81C>G
- Canonical SPDI
- NC_000019.10:11100235:C: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.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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 |
4059 | 4334 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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 (20) |
reviewed by expert panel
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May 6, 2022 | RCV000211569.32 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 29, 2024 | RCV000588365.10 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jun 1, 2024 | RCV001283999.23 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 29, 2023 | RCV002426989.3 | |
See cases
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Likely pathogenic (1) |
criteria provided, single submitter
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Dec 5, 2021 | RCV003128396.2 |
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
Help
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
Help
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
Help
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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Pathogenic
(May 06, 2022)
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reviewed by expert panel
Method: curation
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Hypercholesterolemia, familial, 1
(Semidominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV002817166.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
NM_000527.5(LDLR):c.81C>G (p.Cys27Trp) variant is classified as pathogenic for Familial Hypercholesterolemia by applying evidence code PM1, PM2, PS3_moderate, PS4, PP1, PP3 and PP4 as defined by … (more)
NM_000527.5(LDLR):c.81C>G (p.Cys27Trp) variant is classified as pathogenic for Familial Hypercholesterolemia by applying evidence code PM1, PM2, PS3_moderate, PS4, PP1, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM1: Variant meets PM2 and alters Cys27, one of the cysteine residues listed. PM2: PopMax MAF = 0.00003518 (0.004%) in European (non-Finnish) exomes (gnomAD v2.1.1). PS3_moderate: PMID:1301956 - Level 2 assay - study on hmz patient's fibroblast cell, LDLR activity value range: 15-30%. PS4: Variant meets PM2. Variant identified in >15 index cases - 1 case from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) with Simon Broome possible - 1 case from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with Dutch lipid clinic network >=6 - 2 cases from Robarts Research Institute with Dutch lipid clinic network >=6 - 2 cases from Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca with Dutch lipid clinic network >=6 -as well as >10 cases from (PMID: 1301956, 9259195, 11317361, 11668627, 14974088, 16250003, 23375686, 25463123, 27497240, 27824480, 31345425) PP1: Variant segregates with FH phenotype in at least 2 informative meiosis (minimum 2) from 2 families from different labs (Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca, and Laboratory of Genetics and Molecular Cardiology) PP3: REVEL = 0.759 PP4: Variant meets PM2 and is identified in several index case who fulfil SB/DLCN>6/MedPed/other criteria for FH from different labs (see PS4), after alternative causes of high cholesterol were excluded. (less)
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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: SCV000294455.2
First in ClinVar: Jul 29, 2016 Last updated: Sep 30, 2017 |
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
Observation 5:
Number of individuals with the variant: 1
Observation 6:
Number of individuals with the variant: 1
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Likely pathogenic
(-)
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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:
germline
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Robarts Research Institute, Western University
Accession: SCV000484735.1
First in ClinVar: Dec 17, 2016 Last updated: Dec 17, 2016 |
Number of individuals with the variant: 1
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Likely benign
(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: SCV000503098.1
First in ClinVar: Dec 17, 2016 Last updated: Dec 17, 2016 |
Comment:
subject mutated among 2600 FH index cases screened = 1 / Software predictions: Damaging
Number of individuals with the variant: 1
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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: SCV000540716.1
First in ClinVar: Apr 08, 2017 Last updated: Apr 08, 2017 |
Comment:
Disrupt disulfide bridge between Cys27 and Cys39.
Number of individuals with the variant: 1
Clinical Features:
Hypercholesterolemia (present)
Age: 0-9 years
Sex: female
Ethnicity/Population group: Caucasian
Geographic origin: Czech Republic
Tissue: Whole blood
Method: ADH Master kit (Multiplicom)
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Pathogenic
(Mar 30, 2017)
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criteria provided, single submitter
Method: clinical testing
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Familial Hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille
Accession: SCV000583627.1
First in ClinVar: Apr 08, 2017 Last updated: Apr 08, 2017
Comment:
ACMG Guidelines: Pathogenic (ii)
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Comment:
ACMG Guidelines: Pathogenic (ii)
Number of individuals with the variant: 5
Clinical Features:
Hyperbetalipoproteinemia (present) , Hypercholesterolemia (present)
Indication for testing: Familial Hypercholesterolemia
Sex: mixed
Geographic origin: France
Comment on evidence:
Dutch Lipid Clinic Scoring : Probable FH
Secondary finding: no
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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: unknown
Allele origin:
germline
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Laboratory of Genetics and Molecular Cardiology, University of São Paulo
Study: HipercolBrasil
Accession: SCV000588483.1 First in ClinVar: Aug 13, 2017 Last updated: Aug 13, 2017 |
Observation 1:
Comment on evidence:
%MAF(ExAC):0.001652
Observation 2:
Comment on evidence:
Assay description:Hmz patients' fibroblasts, 125I-LDL assays
Result:
15-30% LDLR activity
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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: unknown
Allele origin:
germline
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Fundacion Hipercolesterolemia Familiar
Study: SAFEHEART
Accession: SCV000607412.1 First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
Observation 1:
Comment on evidence:
%MAF(ExAC):0.001652
Observation 2:
Comment on evidence:
Hmz patients' fibroblasts, 125I-LDL assays
Result:
15-30% LDLR activity
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Pathogenic
(Jan 12, 2017)
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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: SCV000697253.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The LDLR c.81C>G (p.Cys27Trp) variant (alternatively also known as C6W and FH San Francisco) substitutes a Cys residue located in LDL receptor class … (more)
Variant summary: The LDLR c.81C>G (p.Cys27Trp) variant (alternatively also known as C6W and FH San Francisco) substitutes a Cys residue located in LDL receptor class A repeat which forms ligand binding domain (InterPro, Klancar_2015, Bertolini_2013, Hobbs_1992). The ligand-binding domain contains seven or eight 40-amino acid LDLR class A (cysteine-rich) repeats, each of which contains a coordinated calcium ion and six cysteine residues involved in disulphide bond formation (InterPro, PMID: 6091915). Therefore, this variant is predicted to be deleterious for protein function as it breaks down one of the disulphide bonds. 5/5 in silico tools also predict damaging outcome for this variant. This variant was found in 2/121358 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). In literature, this variant is widely reported as a pathogenic variant found mainly in FH patients of European origin (Klancar_2015, Mollaki_2014,Kolansky_2008, Bertolini_2013, Day_1997, Hobbs_1992). Genotype-phenotype correlation study showed that this variant causes a milder disease (Mollaki_2014). A functional study showed that this variant leads to impaired LDL receptor activity (Hobbs_1992). Multiple reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as Pathogenic. (less)
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Likely pathogenic
(Aug 06, 2018)
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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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Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen
Accession: SCV000987032.1
First in ClinVar: Aug 31, 2019 Last updated: Aug 31, 2019 |
Comment:
The mutation at the protein level at position 27 (position 6 of the mature protein) leads to the amino acid change of cysteine to tryptophan … (more)
The mutation at the protein level at position 27 (position 6 of the mature protein) leads to the amino acid change of cysteine to tryptophan (p.Cys27Trp, old nomenclature: p.Cys6Trp). This change has already been described in the literature as a San Francisco allele and is associated with elevated cholesterol and LDL-C levels. Impairment of LDL receptor activity has been demonstrated. We observed a patient with that kind of mutation with average values of TC = 330 and LDL-C of 280 mg/dl. PMID: 1301956, 23375686, 27497240 (less)
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Pathogenic
(-)
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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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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000987521.1
First in ClinVar: Sep 06, 2019 Last updated: Sep 06, 2019 |
|
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Likely pathogenic
(Jan 21, 2019)
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criteria provided, single submitter
Method: research
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Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
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Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia
Accession: SCV001432579.1
First in ClinVar: Sep 19, 2020 Last updated: Sep 19, 2020 |
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Dutch Lipid Clinic Network Criteria score (present) , low-density lipoprotein cholesterol level (present)
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Dutch Lipid Clinic Network Criteria score (present) , low-density lipoprotein cholesterol level (present)
Observation 3:
Number of individuals with the variant: 1
Clinical Features:
Dutch Lipid Clinic Network Criteria score (present) , low-density lipoprotein cholesterol level (present)
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Likely pathogenic
(Oct 02, 2018)
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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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Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV001434982.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
This c.81C>G (p.Cys27Trp) variant in the LDLR gene has been reported in multiple unrelated individuals with familial hypercholesterolemia (PMID: 1301956, 9259195, 11317361, 11668627, 16250003, 23375686) … (more)
This c.81C>G (p.Cys27Trp) variant in the LDLR gene has been reported in multiple unrelated individuals with familial hypercholesterolemia (PMID: 1301956, 9259195, 11317361, 11668627, 16250003, 23375686) and is extremely rare in the general population. Functional studies have reported that the mutant LDLR protein retains 15-30% of receptor activity compared with wildtype LDLR protein (PMID: 1301956). Therefore, this c.81C>G (p.Cys27Trp) variant in the LDLR gene is classified as likely pathogenic. (less)
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Pathogenic
(Jun 30, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001469538.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. This variant is statistically … (more)
Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. Assessment of experimental evidence suggests this variant results in abnormal protein function. (less)
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Likely pathogenic
(May 24, 2021)
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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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Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II
Accession: SCV001653580.1
First in ClinVar: Jun 08, 2021 Last updated: Jun 08, 2021 |
Number of individuals with the variant: 1
Ethnicity/Population group: Caucasian
Geographic origin: Italy
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Pathogenic
(Jan 22, 2020)
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criteria provided, single submitter
Method: curation
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Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001422932.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 02, 2022 |
Comment:
The p.Cys27Trp variant in LDLR has been reported in 54 individuals (including 47 Greek individuals) with Familial Hypercholesterolemia (PMID: 11317361, 11668627, 9259195, 1301956, 25463123, 19026292), … (more)
The p.Cys27Trp variant in LDLR has been reported in 54 individuals (including 47 Greek individuals) with Familial Hypercholesterolemia (PMID: 11317361, 11668627, 9259195, 1301956, 25463123, 19026292), segregated with disease in 37 affected relatives from 18 families, and has been identified in 0.003518% (4/113686) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs2228671). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported pathogenic, likely pathogenic, and likely benign in ClinVar (Variation ID: 226304). In vitro functional studies provide some evidence that the p.Cys27Trp variant may slightly impact protein function (PMID: 1301956). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for Familial Hypercholesterolemia in an autosomal dominant manner based on cosegregation with Familial Hypercholesterolemia and greater prevalence in individuals with Familial Hypercholesterolemia than in control cohorts. ACMG/AMP Criteria applied: PS4, PP1_Strong, PP3, PS3_supporting (Richards 2015). (less)
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Pathogenic
(Dec 23, 2021)
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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: SCV002504158.2
First in ClinVar: Apr 29, 2022 Last updated: Mar 04, 2023 |
Comment:
Also known as p.(C6W) or FH San Francisco; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense … (more)
Also known as p.(C6W) or FH San Francisco; 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; Participates in disulfide bonding with another cysteine residue which is critical for correct protein structure, and is located in the LDL-receptor class A1 repeat domain which is necessary for ligand binding (Sudhof et al., 1985; Rudenko et al., 2002); Reported in ClinVar (ClinVar Variant ID# 226304; ClinVar); This variant is associated with the following publications: (PMID: 17539906, 19062533, 11317361, 11668627, 9259195, 27497240, 16250003, 25463123, 19026292, 14974088, 21925044, 27578104, 27765764, 27824480, 22883975, 17426749, 22836074, 24075752, 21310417, 1301956, 29284604, 19060911, 31447099, 32977124, 32041611, 32719484, 33740630, 34037665, 2988123, 12459547, 23375686) (less)
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Pathogenic
(Jan 29, 2024)
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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: SCV001225810.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 27 of the LDLR … (more)
This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 27 of the LDLR protein (p.Cys27Trp). This variant is present in population databases (rs2228671, gnomAD 0.004%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 11668627, 14974088, 19026292, 25463123, 27497240, 27824480). This variant is also known as C6W. ClinVar contains an entry for this variant (Variation ID: 226304). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. 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). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 29, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV001734617.2
First in ClinVar: Jun 19, 2021 Last updated: Feb 14, 2024 |
Comment:
This missense variant (also known as p.Cys6Trp in the mature protein) replaces cysteine with tryptophan at codon 27 in the LDLR type A repeat 1 … (more)
This missense variant (also known as p.Cys6Trp in the mature protein) replaces cysteine with tryptophan at codon 27 in the LDLR type A repeat 1 of the LDLR protein. This variant alters a conserved cysteine residue that is critical for proper protein folding and function (PMID: 2088165, 6091915, 15952897). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study performed with cells from an individual affected with homozygous familial hypercholesterolemia has indicated that the mutant protein retains 15-30% of receptor activity compared with the wild type LDLR protein (PMID: 1301956). This variant has been observed in over 60 individuals affected with familial hypercholesterolemia (PMID: 1301956, 9259195, 11317361, 11668627, 14974088, 16250003, 23375686, 25463123, 27497240, 27824480, 31345425, 33807407, 34297352). This variant has also been observed in compound heterozygous state in individuals affected with homozygous familial hypercholesterolemia, indicating that this variant contributes to disease (PMID: 19026292, 23375686). This variant has been identified in 4/250746 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Jun 01, 2024)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001501230.21
First in ClinVar: Mar 14, 2021 Last updated: Aug 04, 2024 |
Comment:
LDLR: PM1, PM2, PP4:Moderate, PS4:Moderate, PP3, PS3:Supporting
Number of individuals with the variant: 8
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Pathogenic
(Jun 14, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002580113.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS4_VSTR, PS3_MOD, PM2_SUP, PP3
|
Number of individuals with the variant: 1
Sex: female
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Pathogenic
(Jul 20, 2021)
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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:
paternal
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV002764773.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Number of individuals with the variant: 1
Clinical Features:
Abnormal facial shape (present) , Failure to thrive (present) , Motor delay (present) , Fetal growth restriction (present)
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Likely pathogenic
(Dec 05, 2021)
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criteria provided, single submitter
Method: clinical testing
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see cases
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University Hospital Muenster
Accession: SCV003804883.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
ACMG categories: PM1,PM2,PP2,PP4,PP5,BP1
Number of individuals with the variant: 1
Clinical Features:
Hypercholesterolemia (present)
Age: 10-19 years
Sex: female
Tissue: blood
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Pathogenic
(Aug 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003827102.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Jul 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
(Semidominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004820112.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This missense variant (also known as p.Cys6Trp in the mature protein) replaces cysteine with tryptophan at codon 27 in the LDLR type A repeat 1 … (more)
This missense variant (also known as p.Cys6Trp in the mature protein) replaces cysteine with tryptophan at codon 27 in the LDLR type A repeat 1 of the LDLR protein. This variant alters a conserved cysteine residue that is critical for proper protein folding and function (PMID: 2088165, 6091915, 15952897). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study performed with cells from an individual affected with homozygous familial hypercholesterolemia has indicated that the mutant protein retains 15-30% of receptor activity compared with the wild type LDLR protein (PMID: 1301956). This variant has been observed in over 60 individuals affected with familial hypercholesterolemia (PMID: 1301956, 9259195, 11317361, 11668627, 14974088, 16250003, 23375686, 25463123, 27497240, 27824480, 31345425, 33807407, 34297352). This variant has also been observed in compound heterozygous state in individuals affected with homozygous familial hypercholesterolemia, indicating that this variant contributes to disease (PMID: 19026292, 23375686). This variant has been identified in 4/250746 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
Number of individuals with the variant: 3
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Pathogenic
(Sep 29, 2023)
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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: SCV002680121.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.C27W pathogenic mutation (also known as c.81C>G), located in coding exon 2 of the LDLR gene, results from a C to G substitution at … (more)
The p.C27W pathogenic mutation (also known as c.81C>G), located in coding exon 2 of the LDLR gene, results from a C to G substitution at nucleotide position 81. The cysteine at codon 27 is replaced by tryptophan, an amino acid with highly dissimilar properties. Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Villéger L. Hum Mutat. 2002;20(2):81-7). This particular cysteine alteration has been reported in numerous familial hypercholesterolemia cohorts (e.g., Miltiadous G et al. Hum. Mutat. 2001;17:432-3; Dedoussis GV et al. Eur. J. Clin. Invest. 2004;34:402-9; Kolansky DM et al. Am. J. Cardiol. 2008;102:1438-43; Mollaki V et al. Atherosclerosis. 2014;237:798-804). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 1 (Ambry internal data). Two functional studies have indicated that this alteration leads to reduced LDLR activity, but data were not provided (Hobbs HH et al. Hum. Mutat. 1992;1:445-66; Dedoussis GV et al. Eur. J. Clin. Invest. 2004;34:402-9). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Jun 13, 2024)
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criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV005090998.1
First in ClinVar: Aug 04, 2024 Last updated: Aug 04, 2024 |
Comment:
PM1, PM2, PM5, PP3, PP5- This variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID: 226304). Low frequency in gnomAD population … (more)
PM1, PM2, PM5, PP3, PP5- This variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID: 226304). Low frequency in gnomAD population databases. (less)
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Pathogenic
(Apr 16, 2012)
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no assertion criteria provided
Method: clinical testing
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Familial hypercholesterolemia
Affected status: yes
Allele origin:
germline
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Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital
Accession: SCV000268538.1
First in ClinVar: May 22, 2016 Last updated: May 22, 2016 |
Number of individuals with the variant: 1
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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: SCV000606006.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
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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 |
---|---|---|---|---|
Genetic spectrum of familial hypercholesterolemia and correlations with clinical expression: Implications for diagnosis improvement. | Di Taranto MD | Clinical genetics | 2021 | PMID: 34297352 |
Molecular Genetic Approach and Evaluation of Cardiovascular Events in Patients with Clinical Familial Hypercholesterolemia Phenotype from Romania. | Vlad CE | Journal of clinical medicine | 2021 | PMID: 33807407 |
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 |
Six years' experience with LipidSeq: clinical and research learnings from a hybrid, targeted sequencing panel for dyslipidemias. | Dron JS | BMC medical genomics | 2020 | PMID: 32041611 |
Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network. | eMERGE Consortium. Electronic address: agibbs@bcm.edu | American journal of human genetics | 2019 | PMID: 31447099 |
Risk of Premature Atherosclerotic Disease in Patients With Monogenic Versus Polygenic Familial Hypercholesterolemia. | Trinder M | Journal of the American College of Cardiology | 2019 | PMID: 31345425 |
The molecular genetic background of familial hypercholesterolemia: data from the Slovak nation-wide survey. | Gabčová D | Physiological research | 2017 | PMID: 27824480 |
Polygenic Versus Monogenic Causes of Hypercholesterolemia Ascertained Clinically. | Wang J | Arteriosclerosis, thrombosis, and vascular biology | 2016 | PMID: 27765764 |
Identification and molecular characterisation of Lausanne Institutional Biobank participants with familial hypercholesterolaemia - a proof-of-concept study. | Maurer F | Swiss medical weekly | 2016 | PMID: 27497240 |
Familial Hypercholesterolemia in Greek children and their families: genotype-to-phenotype correlations and a reconsideration of LDLR mutation spectrum. | Mollaki V | Atherosclerosis | 2014 | PMID: 25463123 |
Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. | Bertolini S | Atherosclerosis | 2013 | PMID: 23375686 |
Genetic analysis of familial hypercholesterolaemia in Western Australia. | Hooper AJ | Atherosclerosis | 2012 | PMID: 22883975 |
An APEX-based genotyping microarray for the screening of 168 mutations associated with familial hypercholesterolemia. | Dušková L | Atherosclerosis | 2011 | PMID: 21310417 |
Characterization of low density lipoprotein receptor (LDLR) gene mutations in Albania. | Diakou M | Archives of medical science : AMS | 2010 | PMID: 22371747 |
Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. | Aulchenko YS | Nature genetics | 2009 | PMID: 19060911 |
Longitudinal evaluation and assessment of cardiovascular disease in patients with homozygous familial hypercholesterolemia. | Kolansky DM | The American journal of cardiology | 2008 | PMID: 19026292 |
Update and analysis of the University College London low density lipoprotein receptor familial hypercholesterolemia database. | Leigh SE | Annals of human genetics | 2008 | PMID: 18325082 |
Update of the molecular basis of familial hypercholesterolemia in The Netherlands. | Fouchier SW | Human mutation | 2005 | PMID: 16250003 |
Structure and physiologic function of the low-density lipoprotein receptor. | Jeon H | Annual review of biochemistry | 2005 | PMID: 15952897 |
FH clinical phenotype in Greek patients with LDL-R defective vs. negative mutations. | Dedoussis GV | European journal of clinical investigation | 2004 | PMID: 15200491 |
Molecular characterization of familial hypercholesterolemia in German and Greek patients. | Dedoussis GV | Human mutation | 2004 | PMID: 14974088 |
Low density lipoprotein receptor (LDLR) gene mutations in Canadian subjects with familial hypercholesterolemia, but not of French descent. | Wang J | Human mutation | 2001 | PMID: 11668627 |
Characterization and geographic distribution of the low density lipoprotein receptor (LDLR) gene mutations in northwestern Greece. | Miltiadous G | Human mutation | 2001 | PMID: 11317361 |
Evidence for a third genetic locus causing familial hypercholesterolemia. A non-LDLR, non-APOB kindred. | Haddad L | Journal of lipid research | 1999 | PMID: 10357843 |
Spectrum of LDL receptor gene mutations in heterozygous familial hypercholesterolemia. | Day IN | Human mutation | 1997 | PMID: 9259195 |
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 |
A missense mutation in the low density lipoprotein receptor gene causes familial hypercholesterolemia in Sephardic Jews. | Leitersdorf E | Human genetics | 1993 | PMID: 8462973 |
Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. | Hobbs HH | Human mutation | 1992 | PMID: 1301956 |
The LDL receptor locus in familial hypercholesterolemia: mutational analysis of a membrane protein. | Hobbs HH | Annual review of genetics | 1990 | PMID: 2088165 |
The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA. | Yamamoto T | Cell | 1984 | PMID: 6091915 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/1b6349ea-5843-44ac-bd0b-6dbe58fb0da4 | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/30fb3028-5e83-4804-985a-bf2531cc1774 | - | - | - | - |
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Text-mined citations for this variant ...
HelpRecord last updated Aug 04, 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.