ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.131G>A (p.Trp44Ter)
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.131G>A (p.Trp44Ter)
Variation ID: 3741 Accession: VCV000003741.35
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11100286 (GRCh38) [ NCBI UCSC ] 19: 11210962 (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 Jun 20, 2015 May 1, 2024 Nov 9, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000527.5:c.131G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Trp44Ter nonsense NM_001195798.2:c.131G>A NP_001182727.1:p.Trp44Ter nonsense NM_001195799.2:c.131G>A NP_001182728.1:p.Trp44Ter nonsense NM_001195800.2:c.131G>A NP_001182729.1:p.Trp44Ter nonsense NM_001195803.2:c.131G>A NP_001182732.1:p.Trp44Ter nonsense NC_000019.10:g.11100286G>A NC_000019.9:g.11210962G>A NG_009060.1:g.15906G>A LRG_274:g.15906G>A LRG_274t1:c.131G>A LRG_274p1:p.Trp44Ter - Protein change
- W44*
- Other names
- W23*
- NP_000518.1:p.W44*
- Canonical SPDI
- NC_000019.10:11100285:G:A
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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
Help
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
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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 |
4064 | 4339 |
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/Likely pathogenic (16) |
criteria provided, multiple submitters, no conflicts
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Apr 10, 2023 | RCV000003939.30 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 23, 2015 | RCV000844726.4 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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May 5, 2021 | RCV000786354.10 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Nov 9, 2023 | RCV000775022.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 17, 2022 | RCV002381241.2 |
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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Likely pathogenic
(-)
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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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Institute for Integrative and Experimental Genomics, University of Luebeck
Accession: SCV000212131.1
First in ClinVar: Jun 20, 2015 Last updated: Jun 20, 2015 |
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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: SCV000583633.1
First in ClinVar: Apr 16, 2017 Last updated: Apr 16, 2017
Comment:
ACMG Guidelines: Pathogenic (i)
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Comment:
ACMG Guidelines: Pathogenic (ii)
Number of individuals with the variant: 7
Clinical Features:
Hyperbetalipoproteinemia (present) , Hypercholesterolemia (present)
Indication for testing: Familial Hypercholesterolemia
Sex: mixed
Geographic origin: France
Comment on evidence:
Dutch Lipid Clinic Scoring : Definite FH
Secondary finding: no
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Pathogenic
(Mar 23, 2015)
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criteria provided, single submitter
Method: clinical testing
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Homozygous familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000271381.3
First in ClinVar: May 29, 2016 Last updated: Aug 31, 2019 |
Comment:
The p.Trp44X variant in LDLR has been reported in a large number (>500) of indiv iduals with hypercholesterolemia (Hobbs 1992, Huijgen 2010, Chmara 2010, Duskova … (more)
The p.Trp44X variant in LDLR has been reported in a large number (>500) of indiv iduals with hypercholesterolemia (Hobbs 1992, Huijgen 2010, Chmara 2010, Duskova 2011, Fouchier 2015). It was absent from large population studies. This nonsens e variant leads to a premature termination codon at position 44, which is predic ted to lead to a truncated or absent protein. Heterozygous loss of LDLR function is an established disease mechanism in familial hypercholesterolemia. In summar y, this variant meets our criteria to be classified as pathogenic for hyperchole sterolemia in an autosomal dominant manner (http://www.partners.org/personalized medicince/LMM) based upon the predicted impact to the protein, its presence in a large number of affected individuals, and absence from controls. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jan 23, 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: SCV001432627.1
First in ClinVar: Sep 19, 2020 Last updated: Sep 19, 2020 |
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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Pathogenic
(Nov 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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MGZ Medical Genetics Center
Accession: SCV002579618.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PVS1, PS4, PM2_SUP
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Number of individuals with the variant: 1
Sex: female
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Pathogenic
(May 05, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001715233.2
First in ClinVar: Jun 15, 2021 Last updated: Jun 03, 2023 |
Comment:
PVS1, PS4, PM2, PS3_moderate, PM3_supporting
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Pathogenic
(Oct 28, 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: SCV003827202.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Nov 09, 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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Invitae
Accession: SCV000544649.6
First in ClinVar: Apr 16, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Trp44*) in the LDLR gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Trp44*) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hypercholesterolemia (PMID: 1301956, 11668627, 16542394, 20145306, 20506408, 21382890, 22390909, 22698793). ClinVar contains an entry for this variant (Variation ID: 3741). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 10, 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: SCV004820118.1
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 variant (also known as W23X in the mature protein and as FH Cincinnati-5) changes a single nucleotide in exon 2 of the LDLR gene, … (more)
This variant (also known as W23X in the mature protein and as FH Cincinnati-5) changes a single nucleotide in exon 2 of the LDLR gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over 60 individuals affected with familial hypercholesterolemia (PMID: 1301956, 11668627, 16542394, 20145306, 20506408, 21382890, 22390909, 22698793). This variant has also been observed in compound heterozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 31048103). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
Number of individuals with the variant: 2
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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: SCV000294478.2
First in ClinVar: Jul 29, 2016 Last updated: Oct 13, 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
Observation 5:
Number of individuals with the variant: 1
Observation 6:
Number of individuals with the variant: 1
Observation 7:
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: SCV000484698.1
First in ClinVar: Dec 17, 2016 Last updated: Dec 17, 2016 |
Number of individuals with the variant: 2
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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: SCV000503103.1
First in ClinVar: Dec 17, 2016 Last updated: Dec 17, 2016 |
Comment:
subjects mutated among 2600 FH index cases screened = 10 , family members = 2 with co-segregation / FH-Cincinnati-5, 2 to 5% LDLR activity
Number of individuals with the variant: 10
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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:
inherited
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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: SCV000540718.1
First in ClinVar: Apr 08, 2017 Last updated: Apr 08, 2017 |
Number of individuals with the variant: 27
Clinical Features:
Hypercholesterolemia (present) , Ischemic stroke (present)
Family history: yes
Age: 4-51 years
Sex: mixed
Ethnicity/Population group: Caucasian
Geographic origin: Czech Republic
Tissue: Whole blood
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Pathogenic
(Sep 19, 2017)
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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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Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV000839974.1
First in ClinVar: Oct 13, 2018 Last updated: Oct 13, 2018 |
Comment:
This c.131G>A (p.Trp44*) variant in the LDLR gene is predicted to is predicted to introduce a premature translation termination codon. This variant has been reported … (more)
This c.131G>A (p.Trp44*) variant in the LDLR gene is predicted to is predicted to introduce a premature translation termination codon. This variant has been reported in multiple patients with familial hypercholesterolemia (PMID: 1301956, 8850176). The c.131G>A (p.Trp44*) variant in the LDLR gene is classified as pathogenic. (less)
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Pathogenic
(Jun 28, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001748774.1
First in ClinVar: Jul 10, 2021 Last updated: Jul 10, 2021 |
Comment:
Variant summary: LDLR c.131G>A (p.Trp44X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: LDLR c.131G>A (p.Trp44X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251254 control chromosomes. In a cross sectional ascertainment, c.131G>A has been widely reported in the literature in individuals affected with Familial Hypercholesterolemia (example, Hobbs_1992, Huijgen_2012, Luirink_2019, Dron_2020). These data indicate that the variant is likely to be associated with disease. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Oct 20, 2020)
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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: SCV001789004.1
First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
Comment:
Not observed in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene … (more)
Not observed in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect as this variant results in a null allele (Hobbs et al., 1992); Reported in ClinVar (ClinVar Variant ID# 3741; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 32665702, 32331935, 32719484, 32041611, 31447099, 31048103, 22390909, 26036859, 12417285, 9157944, 8645371, 8850176, 1301956, 25525159) (less)
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Pathogenic
(Feb 01, 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: SCV000909119.2
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This variant (also known as W23X in the mature protein and as FH Cincinnati-5) changes a single nucleotide in exon 2 of the LDLR gene, … (more)
This variant (also known as W23X in the mature protein and as FH Cincinnati-5) changes a single nucleotide in exon 2 of the LDLR gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over 60 individuals affected with familial hypercholesterolemia (PMID: 1301956, 11668627, 16542394, 20145306, 20506408, 21382890, 22390909, 22698793). This variant has also been observed in compound heterozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 31048103). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Mar 30, 2023)
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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 Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002503801.2
First in ClinVar: Apr 28, 2022 Last updated: Apr 15, 2024 |
Comment:
This sequence change creates a premature termination codon at position 44 in exon 2 (of 18) of LDLR, p.(Trp44*), also known as p.Trp23* and FH … (more)
This sequence change creates a premature termination codon at position 44 in exon 2 (of 18) of LDLR, p.(Trp44*), also known as p.Trp23* and FH Cincinnati-5. It is expected to result in nonsense mediated decay, and loss of function is a well-established mechanism of disease for this gene (ClinGen). The variant is absent in a large population cohort (gnomAD v2.1 and v3.1). The variant is a recurrent mutation that has been identified in individuals with either homozygous or heterozygous familial hypercholesterolaemia, and segregates with disease in multiple families. Additionally, loss of LDL receptor activity has been identified in patient fibroblasts from an individual with this variant (PMID: 8850176, 1301956). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PP1_Strong, PM2_Supporting, PP4. (less)
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Pathogenic
(Aug 17, 2022)
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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: SCV002689744.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.W44* pathogenic mutation (also known as c.131G>A), located in coding exon 2 of the LDLR gene, results from a G to A substitution at … (more)
The p.W44* pathogenic mutation (also known as c.131G>A), located in coding exon 2 of the LDLR gene, results from a G to A substitution at nucleotide position 131. This changes the amino acid from a tryptophan to a stop codon within coding exon 2. This mutation has been reported in multiple unrelated individuals with familial hypercholesterolemia (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Brusgaard K et al. Clin. Genet., 2006 Mar;69:277-83; van der Graaf A et al. Circulation, 2011 Mar;123:1167-73; Wang J et al. Hum. Mutat., 2001 Oct;18:359; Chmara M et al. J. Appl. Genet., 2010;51:95-106; Tichý L et al. Atherosclerosis, 2012 Aug;223:401-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Jul 22, 2008)
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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: SCV000268535.1
First in ClinVar: May 21, 2016 Last updated: May 21, 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: SCV000606021.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV000733811.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
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Pathogenic
(Oct 05, 1986)
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no assertion criteria provided
Method: literature only
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HYPERCHOLESTEROLEMIA, FAMILIAL, 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000024104.3
First in ClinVar: Apr 04, 2013 Last updated: Jun 23, 2019 |
Comment on evidence:
In patients with familial hypercholesterolemia (FHCL1; 143890), Hobbs et al. (1992) identified a trp23-to-ter mutation in the LDLR gene.
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Pathogenic
(Aug 16, 2016)
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no assertion criteria provided
Method: provider interpretation
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not provided
Affected status: unknown
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000925140.1
First in ClinVar: Jun 30, 2019 Last updated: Jun 30, 2019 |
Comment:
The patient had genetic testing for the familial hypercholesterolemia panel. The test included sequencing of four genes associated with familial hypercholesterolemia: LDLR, APOB, PCSK9 and … (more)
The patient had genetic testing for the familial hypercholesterolemia panel. The test included sequencing of four genes associated with familial hypercholesterolemia: LDLR, APOB, PCSK9 and LDLRAP1. Results showed that the following variant was identified (see report below): p.Trp44* (c.131G>A) in the LDLR gene (NM_000527.4) The lab classifies this variant as pathogenic. Given sufficient case data and the loss of function nature of this variant we consider this variant pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least nine unrelated cases of FH (not including this patient's family). This amounts to strong case data. Some of these individuals are reported as p.W23X in the literature due to alternate transcript terminology. See PMIDs: 1301956, 22390909, 21382890, 11668627, 22698793, 20145306, 16542394, 20506408). (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001918524.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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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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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 |
Coronary computed tomography angiography and echocardiography in children with homozygous familial hypercholesterolemia. | Luirink IK | Atherosclerosis | 2019 | PMID: 31048103 |
Analysis of LDLR variants from homozygous FH patients carrying multiple mutations in the LDLR gene. | Jiang L | Atherosclerosis | 2017 | PMID: 28645073 |
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 |
Current novel-gene-finding strategy for autosomal-dominant hypercholesterolaemia needs refinement. | Fouchier SW | Journal of medical genetics | 2015 | PMID: 25412742 |
The molecular basis of familial hypercholesterolemia in the Czech Republic: spectrum of LDLR mutations and genotype-phenotype correlations. | Tichý L | Atherosclerosis | 2012 | PMID: 22698793 |
Cardiovascular risk in relation to functionality of sequence variants in the gene coding for the low-density lipoprotein receptor: a study among 29,365 individuals tested for 64 specific low-density lipoprotein-receptor sequence variants. | Huijgen R | European heart journal | 2012 | PMID: 22390909 |
Molecular basis of autosomal dominant hypercholesterolemia: assessment in a large cohort of hypercholesterolemic children. | van der Graaf A | Circulation | 2011 | PMID: 21382890 |
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 |
Functionality of sequence variants in the genes coding for the low-density lipoprotein receptor and apolipoprotein B in individuals with inherited hypercholesterolemia. | Huijgen R | Human mutation | 2010 | PMID: 20506408 |
Molecular characterization of Polish patients with familial hypercholesterolemia: novel and recurrent LDLR mutations. | Chmara M | Journal of applied genetics | 2010 | PMID: 20145306 |
Molecular genetic analysis of 1053 Danish individuals with clinical signs of familial hypercholesterolemia. | Brusgaard K | Clinical genetics | 2006 | PMID: 16542394 |
Molecular genetic analysis of familial hypercholesterolemia: spectrum and regional difference of LDL receptor gene mutations in Japanese population. | Yu W | Atherosclerosis | 2002 | PMID: 12417285 |
The molecular basis of familial hypercholesterolemia in The Netherlands. | Fouchier SW | Human genetics | 2001 | PMID: 11810272 |
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 |
Differences in the phenotype between children with familial defective apolipoprotein B-100 and familial hypercholesterolemia. | Pimstone SN | Arteriosclerosis, thrombosis, and vascular biology | 1997 | PMID: 9157944 |
Phenotypic presentation of the FH-Cincinnati type 5 low density lipoprotein receptor mutation. | Nissen H | Scandinavian journal of clinical and laboratory investigation | 1996 | PMID: 8850176 |
The Trp23-Stop and Trp66-Gly mutations in the LDL receptor gene: common causes of familial hypercholesterolemia in Denmark. | Jensen HK | Atherosclerosis | 1996 | PMID: 8645371 |
Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. | Hobbs HH | Human mutation | 1992 | PMID: 1301956 |
Deletion of exon encoding cysteine-rich repeat of low density lipoprotein receptor alters its binding specificity in a subject with familial hypercholesterolemia. | Hobbs HH | The Journal of biological chemistry | 1986 | PMID: 3020025 |
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Text-mined citations for rs267607213 ...
HelpRecord last updated Sep 01, 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.