subjects mutated among 2600 FH index cases screened = 31 (1 homozygote) , family members = 17 with co-segregation / FH-Libanon, < 2% LDLR Activity
ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.2043C>A (p.Cys681Ter)
Germline
Classification
Help
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.
(33)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
33
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000527.5(LDLR):c.2043C>A (p.Cys681Ter)
Variation ID: 3699 Accession: VCV000003699.44
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19p13.2 19: 11120425 (GRCh38) [ NCBI UCSC ] 19: 11231101 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Apr 4, 2013 Sep 16, 2024 Apr 8, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.2043C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Cys681Ter nonsense NM_001195798.2:c.2043C>A NP_001182727.1:p.Cys681Ter nonsense NM_001195799.2:c.1920C>A NP_001182728.1:p.Cys640Ter nonsense NM_001195800.2:c.1539C>A NP_001182729.1:p.Cys513Ter nonsense NM_001195803.2:c.1606+192C>A intron variant NC_000019.10:g.11120425C>A NC_000019.9:g.11231101C>A NG_009060.1:g.36045C>A LRG_274:g.36045C>A LRG_274t1:c.2043C>A LRG_274p1:p.Cys681Ter - Protein change
- C681*, C513*, C640*
- Other names
-
C660*
FH Lebanese
NP_000518.1:p.C681*
- Canonical SPDI
- NC_000019.10:11120424:C:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| LDLR | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
4076 | 4352 | |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (20) |
criteria provided, multiple submitters, no conflicts
|
Dec 18, 2023 | RCV000003887.35 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jan 31, 2024 | RCV000590806.14 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 22, 2021 | RCV000844750.5 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Apr 8, 2024 | RCV000481771.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 29, 2022 | RCV002415394.2 | |
|
See cases
|
Pathogenic (1) |
criteria provided, single submitter
|
Mar 4, 2021 | RCV004584310.1 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Nov 02, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV000264002.2
First in ClinVar: Oct 11, 2015 Last updated: Mar 31, 2019 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Mar 25, 2016)
|
criteria provided, single submitter
Method: literature only
|
Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
LDLR-LOVD, British Heart Foundation
Accession: SCV000295837.2
First in ClinVar: Jul 29, 2016 Last updated: Mar 31, 2019 |
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
Observation 8:
Number of individuals with the variant: 1
Observation 9:
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Robarts Research Institute, Western University
Accession: SCV000484730.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Number of individuals with the variant: 5
|
|
|
Pathogenic
(Dec 16, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
|
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix
Accession: SCV000503452.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Comment:
subjects mutated among 2600 FH index cases screened = 31 (1 homozygote) , family members = 17 with co-segregation / FH-Libanon, < 2% LDLR Activity
Number of individuals with the variant: 31
|
|
|
Pathogenic
(Nov 05, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
|
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation
Additional submitter:
Centre of Molecular Biology and Gene Therapy, University Hospital Brno
Accession: SCV000540853.1
First in ClinVar: Apr 08, 2017 Last updated: Apr 08, 2017 |
Number of individuals with the variant: 1
Clinical Features:
Hypercholesterolemia (present) , Ischemic stroke (present)
Age: 50-59 years
Sex: male
Ethnicity/Population group: Caucasian
Geographic origin: Czech Republic
Tissue: Whole blood
|
|
|
Pathogenic
(Mar 30, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Familial Hypercholesterolemia
Affected status: yes
Allele origin:
germline
|
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille
Accession: SCV000583922.1
First in ClinVar: Apr 16, 2017 Last updated: Apr 16, 2017
Comment:
ACMG Guidelines: Pathogenic (i)
|
Number of individuals with the variant: 23
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
|
|
|
Pathogenic
(Mar 01, 2016)
|
criteria provided, single submitter
Method: research
|
Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory of Genetics and Molecular Cardiology, University of São Paulo
Study: HipercolBrasil
Accession: SCV000588629.1 First in ClinVar: Aug 13, 2017 Last updated: Aug 13, 2017 |
Observation 1:
Comment on evidence:
%MAF(ExAC):0.0008255
Observation 2:
Comment on evidence:
Assay description:Hmz patients' fibroblasts, 125I-LDL assays
Result:
10% cell surface LDLR, 2-5% LDL-LDLR binding, <2% LDL-LDLR uptake and degradation
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
|
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000987528.1
First in ClinVar: Sep 06, 2019 Last updated: Sep 06, 2019 |
|
|
|
Pathogenic
(Jul 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV001435011.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
The c.2043C>A (p.Cys681*) variant in the LDLR gene has been reported in multiple individual patients with familial Hypercholesterolemia and segregated in the families (PMID: 3025214, … (more)
The c.2043C>A (p.Cys681*) variant in the LDLR gene has been reported in multiple individual patients with familial Hypercholesterolemia and segregated in the families (PMID: 3025214, 1959928, 1453433, 12406975, 22487947). This variant is extremely rare in general population and is predicted to introduce a premature translation termination codon. Therefore, the c.2043C>A (p.Cys681*) variant in the LDLR gene is classified as pathogenic. (less)
|
|
|
Pathogenic
(Nov 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004175941.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
Criteria applied: PVS1,PS4,PM2_SUP,PP1
Clinical Features:
Hypercholesterolemia (present) , Increased LDL cholesterol concentration (present)
Sex: male
|
|
|
Pathogenic
(Mar 06, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001134256.4
First in ClinVar: Jan 05, 2020 Last updated: Jan 06, 2024 |
Comment:
This nonsense variant causes the premature termination of LDLR protein synthesis. The frequency of this variant in the general population, 0.000008 (2/251278 chromosomes, http://gnomad.broadinstitute.org), is … (more)
This nonsense variant causes the premature termination of LDLR protein synthesis. The frequency of this variant in the general population, 0.000008 (2/251278 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported as a Lebanese founder mutation, but has also been identified in multiple other ethnic groups, in individuals and families with familial hypercholesterolemia (PMID: 28873201 (2017), 25461735 (2015), 22487947 (2012), 21145767 (2011), 19319977 (2009), 14974088 (2004), 11668627 (2001), 9664576 (1998), 3025214 (1987)). In a functional study, this variant was found to have a damaging effect on LDLR expression and binding (PMID: 31578082 (2019)). Based on the available information, this variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(May 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004227682.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP1, PS3, PS4_moderate, PVS1
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Nov 14, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003819453.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000285024.11
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Cys681*) 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.Cys681*) 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 present in population databases (rs121908031, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 1959928, 11668627, 19319977, 21145767, 22487947, 25461735). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Cys660*. ClinVar contains an entry for this variant (Variation ID: 3699). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Oct 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001352605.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant changes 1 nucleotide in exon 14 of the LDLR gene, creating a premature translation stop signal. This variant is also known as p.Cys660* … (more)
This variant changes 1 nucleotide in exon 14 of the LDLR gene, creating a premature translation stop signal. This variant is also known as p.Cys660* in the mature protein. This variant is expected to result in an absent or non-functional protein product. Functional studies have shown that this variant causes a significant decrease in LDLR expression and LDL uptake (PMID: 31578082). This variant has been reported in over 100 individuals affected with familial hypercholesterolemia (PMID: 3025214, 11668627, 19319977, 21145767, 25461735, 28502510, 28761763, 28873201, 31578082, 34321884) and is considered to be a founder variant in the Lebanese population (PMID: 19319977). This variant has also been observed in both homozygous and compound heterozygous state with a known pathogenic LDLR variant in multiple individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 28761763, 31578082). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 19319977, 34321884). This variant has been identified in 2/251278 chromosomes 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)
|
|
|
Pathogenic
(Feb 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Homozygous familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000731826.3
First in ClinVar: Apr 09, 2018 Last updated: Apr 20, 2024 |
Comment:
The p.Cys681X variant in LDLR has been reported in >80 individuals with hypercholesterolemia across several studies and segregated with disease in >10 affected relatives (Abifadel … (more)
The p.Cys681X variant in LDLR has been reported in >80 individuals with hypercholesterolemia across several studies and segregated with disease in >10 affected relatives (Abifadel 2009, Banares 2017, Fahed 2011, Jannes 2015, Lehrman 1987, Tichy 2012, Vandrovcova 2013). This variant is considered to be a founder variant in the Lebanese population (Fahed 2016). This variant has also been reported in Clinvar (Variation ID 3699) and has been identified in 1/113666 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 681, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the LDLR gene is an established disease mechanism in familial hypercholesterolemia (FH). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant FH. ACMG/AMP criteria applied: PVS1, PS4, PM2, PP1_Strong. (less)
|
|
|
Pathogenic
(Apr 08, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000568525.7
First in ClinVar: Apr 27, 2017 Last updated: Sep 16, 2024 |
Comment:
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 … (more)
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; Reported many times in the heterozygous, compound heterozygous, and homozygous states in individuals with FH (PMID: 9664576, 9259195, 3025214, 10737984, 11668627, 12406975, 15200491, 28873201, 30179711); Considered a Lebanese founder mutation and may account for greater than 80% of FH cases in this population (PMID: 19319977); Published functional studies suggest a damaging effect on protein expression and binding (PMID: 31578082); Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.(C660X); This variant is associated with the following publications: (PMID: 31447099, 22487947, 25487149, 25525159, 3025214, 9259195, 9664576, 10737984, 11668627, 12406975, 15200491, 28873201, 30179711, 29407885, 34040191, 33303402, 34037665, 32041611, 33740630, 32770674, 33418990, 32231684, 35379577, 32009526, 33955087, 34321884, 15321837, 19319977, 37128917, 31578082) (less)
|
|
|
Pathogenic
(Mar 01, 2016)
|
criteria provided, single submitter
Method: research
|
Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Fundacion Hipercolesterolemia Familiar
Study: SAFEHEART
Accession: SCV000607668.1 First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
Observation 1:
Comment on evidence:
%MAF(ExAC):0.0008255
Observation 2:
Comment on evidence:
Hmz patients' fibroblasts, 125I-LDL assays
Result:
10% cell surface LDLR, 2-5% LDL-LDLR binding, <2% LDL-LDLR uptake and degradation
|
|
|
Pathogenic
(Oct 26, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697220.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The LDLR c.2043C>A (p.Cys681X) variant results in a premature termination codon, predicted to cause a truncated or absent LDLR protein due to nonsense … (more)
Variant summary: The LDLR c.2043C>A (p.Cys681X) variant results in a premature termination codon, predicted to cause a truncated or absent LDLR protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified in the pathogenic spectrum by our laboratory (e.g. p.Trp813X, p.Ser710fsX2 ). Mutation taster predicts a damaging outcome for this variant. This variant was found in 1/121136 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0025031). It was observed in several FH families and showed co-segregation with the disease indicating causality. Moreover, the variant was shown to result in lack of detectable high affinity binding and uptake of LDL, further supporting pathogenicity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(Mar 01, 2016)
|
criteria provided, single submitter
Method: research
|
Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Iberoamerican FH Network
Accession: SCV000748104.1
First in ClinVar: May 19, 2018 Last updated: May 19, 2018
Comment:
Variant present in the databases from Argentina and Uruguay
|
Observation 1:
Comment on evidence:
%MAF(ExAC):0.0008255
Observation 2:
Comment on evidence:
Assay Description:Hmz patients' fibroblasts, 125I-LDL assays
Result:
10% cell surface LDLR, 2-5% LDL-LDLR binding, <2% LDL-LDLR uptake and degradation
|
|
|
Pathogenic
(Sep 16, 2018)
|
criteria provided, single submitter
Method: research
|
not provided
Affected status: yes
Allele origin:
germline
|
Gharavi Laboratory, Columbia University
Accession: SCV000809473.1
First in ClinVar: Apr 27, 2017 Last updated: Apr 27, 2017 |
|
|
|
Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000894178.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Pathogenic
(Aug 09, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
|
Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen
Accession: SCV000987033.1
First in ClinVar: Aug 31, 2019 Last updated: Aug 31, 2019 |
Comment:
The nucleotide substitution c.2043C> A leads to a premature termination of protein synthesis at position 681 and is described as "FH Lebanese allele" in the … (more)
The nucleotide substitution c.2043C> A leads to a premature termination of protein synthesis at position 681 and is described as "FH Lebanese allele" in the literature. The mutation leads to intracellular degradation of the LDL receptor and loss of function. The mutation described here has also been described in patients with hypercholesterolemia and is therefore classified as pathogenic. PMID: 1453433, 3025214 (less)
|
|
|
Pathogenic
(May 11, 2019)
|
criteria provided, single submitter
Method: research
|
Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
|
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia
Accession: SCV001432604.1
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)
Observation 4:
Number of individuals with the variant: 1
Clinical Features:
Dutch Lipid Clinic Network Criteria score (present) , low-density lipoprotein cholesterol level (present)
Observation 5:
Number of individuals with the variant: 1
Clinical Features:
Dutch Lipid Clinic Network Criteria score (present) , low-density lipoprotein cholesterol level (present)
Observation 6:
Number of individuals with the variant: 1
Clinical Features:
Dutch Lipid Clinic Network Criteria score (present) , low-density lipoprotein cholesterol level (present)
Observation 7:
Number of individuals with the variant: 1
Clinical Features:
Dutch Lipid Clinic Network Criteria score (present) , low-density lipoprotein cholesterol level (present)
Observation 8:
Number of individuals with the variant: 1
Clinical Features:
Dutch Lipid Clinic Network Criteria score (present) , low-density lipoprotein cholesterol level (present)
|
|
|
Pathogenic
(Dec 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
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: SCV004818485.1
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 changes 1 nucleotide in exon 14 of the LDLR gene, creating a premature translation stop signal. This variant is also known as p.Cys660* … (more)
This variant changes 1 nucleotide in exon 14 of the LDLR gene, creating a premature translation stop signal. This variant is also known as p.Cys660* in the mature protein. This variant is expected to result in an absent or non-functional protein product. Functional studies have shown that this variant causes a significant decrease in LDLR expression and LDL uptake (PMID: 31578082). This variant has been reported in over 100 individuals affected with familial hypercholesterolemia (PMID: 3025214, 11668627, 19319977, 21145767, 25461735, 28502510, 28761763, 28873201, 31578082, 34321884) and is considered to be a founder variant in the Lebanese population (PMID: 19319977). This variant has also been observed in both homozygous and compound heterozygous state with a known pathogenic LDLR variant in multiple individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 28761763, 31578082). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 19319977, 34321884). This variant has been identified in 2/251278 chromosomes 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: 1
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Pathogenic
(Aug 29, 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: SCV002719816.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.2043C>A (p.C681*) alteration, located in exon 14 (coding exon 14) of the LDLR gene, consists of a C to A substitution at nucleotide position … (more)
The c.2043C>A (p.C681*) alteration, located in exon 14 (coding exon 14) of the LDLR gene, consists of a C to A substitution at nucleotide position 2043. This changes the amino acid from a cysteine (C) to a stop codon at amino acid position 681. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration, also noted as p.C660X or the Lebanese allele, has been reported in individuals with familial hypercholesterolemia and a founder effect was proposed (Lehrman, 1987; Abifadel, 2009; Fahed, 2012). Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Mar 04, 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: SCV002578008.2
First in ClinVar: Oct 08, 2022 Last updated: Jul 07, 2024 |
Comment:
ACMG categories: PVS1,PM2,PP1,PP5
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 21, 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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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV005091025.1
First in ClinVar: Aug 04, 2024 Last updated: Aug 04, 2024 |
Comment:
PVS1, PM2, PP5 - It's pathogenicity has already been established. ClinVar Variation ID 3699.
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Pathogenic
(Jul 13, 2022)
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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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Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005198662.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
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Pathogenic
(May 04, 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: SCV000268655.1
First in ClinVar: May 21, 2016 Last updated: May 21, 2016 |
Number of individuals with the variant: 5
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Pathogenic
(Nov 01, 1991)
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no assertion criteria provided
Method: literature only
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FH LEBANESE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000024052.2
First in ClinVar: Apr 04, 2013 Last updated: Jun 23, 2019 |
Comment on evidence:
Lehrman et al. (1987) analyzed the nature of the LDLR mutation present in high frequency in Lebanon; the frequency of homozygotes is more than 10 … (more)
Lehrman et al. (1987) analyzed the nature of the LDLR mutation present in high frequency in Lebanon; the frequency of homozygotes is more than 10 times higher than in other parts of the world. It was on the basis of studies in Lebanon that Khachadurian (1964) first established the existence of homozygous FHCL1 (143890). Lehrman et al. (1987) demonstrated that the mutation involves a shortened receptor protein containing 3 domains: the region of clustered O-linked carbohydrates, the membrane-spanning region, and the cytoplasmic tail. The defect was attributable to a single nucleotide substitution that creates a premature termination codon at amino acid 660, eliminating 180 residues from the mature protein. The termination codon occurred in the middle of a cysteine-rich sequence that is part of the domain homologous to epidermal growth factor precursor. The truncated protein retains only 2 domains: a complete ligand-binding region (residues 1-292) and a partial epidermal growth factor precursor homology region (residues 293-659). The mutant gene lacks the portions that code for the membrane-spanning region and the cytoplasmic tail. After synthesis, most of the mutant receptor remains within the cell. The mutation creates a new restriction site for the enzyme HinfI, thus permitting diagnosis by Southern blotting of genomic DNA. Lehrman et al. (1987) studied 4 unrelated Arab patients with homozygous familial hypercholesterolemia, 3 from Lebanon and 1 from Syria. They referred to this mutation as the Lebanese allele. In 5 Christian-Arab kindreds in Israel, Oppenheim et al. (1991) found the 'Lebanese' allele in correlation with hypercholesterolemia. In addition, their results suggested the possible existence of an independent factor contributing to elevated LDL cholesterol levels. (less)
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Pathogenic
(Aug 17, 2020)
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no assertion criteria provided
Method: clinical testing
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002086860.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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: SCV000606582.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
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Comment:
Comment:
The c.2043C>A (p.Cys681*) variant in the LDLR gene has been reported in multiple individual patients with familial Hypercholesterolemia and segregated in the families (PMID: 3025214, 1959928, 1453433, 12406975, 22487947). This variant is extremely rare in general population and is predicted to introduce a premature translation termination codon. Therefore, the c.2043C>A (p.Cys681*) variant in the LDLR gene is classified as pathogenic.
Comment:
Criteria applied: PVS1,PS4,PM2_SUP,PP1
Comment:
This nonsense variant causes the premature termination of LDLR protein synthesis. The frequency of this variant in the general population, 0.000008 (2/251278 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported as a Lebanese founder mutation, but has also been identified in multiple other ethnic groups, in individuals and families with familial hypercholesterolemia (PMID: 28873201 (2017), 25461735 (2015), 22487947 (2012), 21145767 (2011), 19319977 (2009), 14974088 (2004), 11668627 (2001), 9664576 (1998), 3025214 (1987)). In a functional study, this variant was found to have a damaging effect on LDLR expression and binding (PMID: 31578082 (2019)). Based on the available information, this variant is classified as pathogenic.
Comment:
PP1, PS3, PS4_moderate, PVS1
Comment:
This sequence change creates a premature translational stop signal (p.Cys681*) 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 present in population databases (rs121908031, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 1959928, 11668627, 19319977, 21145767, 22487947, 25461735). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Cys660*. ClinVar contains an entry for this variant (Variation ID: 3699). For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant changes 1 nucleotide in exon 14 of the LDLR gene, creating a premature translation stop signal. This variant is also known as p.Cys660* in the mature protein. This variant is expected to result in an absent or non-functional protein product. Functional studies have shown that this variant causes a significant decrease in LDLR expression and LDL uptake (PMID: 31578082). This variant has been reported in over 100 individuals affected with familial hypercholesterolemia (PMID: 3025214, 11668627, 19319977, 21145767, 25461735, 28502510, 28761763, 28873201, 31578082, 34321884) and is considered to be a founder variant in the Lebanese population (PMID: 19319977). This variant has also been observed in both homozygous and compound heterozygous state with a known pathogenic LDLR variant in multiple individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 28761763, 31578082). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 19319977, 34321884). This variant has been identified in 2/251278 chromosomes 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.
Comment:
The p.Cys681X variant in LDLR has been reported in >80 individuals with hypercholesterolemia across several studies and segregated with disease in >10 affected relatives (Abifadel 2009, Banares 2017, Fahed 2011, Jannes 2015, Lehrman 1987, Tichy 2012, Vandrovcova 2013). This variant is considered to be a founder variant in the Lebanese population (Fahed 2016). This variant has also been reported in Clinvar (Variation ID 3699) and has been identified in 1/113666 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 681, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the LDLR gene is an established disease mechanism in familial hypercholesterolemia (FH). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant FH. ACMG/AMP criteria applied: PVS1, PS4, PM2, PP1_Strong.
Comment:
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; Reported many times in the heterozygous, compound heterozygous, and homozygous states in individuals with FH (PMID: 9664576, 9259195, 3025214, 10737984, 11668627, 12406975, 15200491, 28873201, 30179711); Considered a Lebanese founder mutation and may account for greater than 80% of FH cases in this population (PMID: 19319977); Published functional studies suggest a damaging effect on protein expression and binding (PMID: 31578082); Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.(C660X); This variant is associated with the following publications: (PMID: 31447099, 22487947, 25487149, 25525159, 3025214, 9259195, 9664576, 10737984, 11668627, 12406975, 15200491, 28873201, 30179711, 29407885, 34040191, 33303402, 34037665, 32041611, 33740630, 32770674, 33418990, 32231684, 35379577, 32009526, 33955087, 34321884, 15321837, 19319977, 37128917, 31578082)
Comment:
Variant summary: The LDLR c.2043C>A (p.Cys681X) variant results in a premature termination codon, predicted to cause a truncated or absent LDLR protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified in the pathogenic spectrum by our laboratory (e.g. p.Trp813X, p.Ser710fsX2 ). Mutation taster predicts a damaging outcome for this variant. This variant was found in 1/121136 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0025031). It was observed in several FH families and showed co-segregation with the disease indicating causality. Moreover, the variant was shown to result in lack of detectable high affinity binding and uptake of LDL, further supporting pathogenicity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
The nucleotide substitution c.2043C> A leads to a premature termination of protein synthesis at position 681 and is described as "FH Lebanese allele" in the literature. The mutation leads to intracellular degradation of the LDL receptor and loss of function. The mutation described here has also been described in patients with hypercholesterolemia and is therefore classified as pathogenic. PMID: 1453433, 3025214
Comment:
This variant changes 1 nucleotide in exon 14 of the LDLR gene, creating a premature translation stop signal. This variant is also known as p.Cys660* in the mature protein. This variant is expected to result in an absent or non-functional protein product. Functional studies have shown that this variant causes a significant decrease in LDLR expression and LDL uptake (PMID: 31578082). This variant has been reported in over 100 individuals affected with familial hypercholesterolemia (PMID: 3025214, 11668627, 19319977, 21145767, 25461735, 28502510, 28761763, 28873201, 31578082, 34321884) and is considered to be a founder variant in the Lebanese population (PMID: 19319977). This variant has also been observed in both homozygous and compound heterozygous state with a known pathogenic LDLR variant in multiple individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 28761763, 31578082). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 19319977, 34321884). This variant has been identified in 2/251278 chromosomes 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.
Comment:
The c.2043C>A (p.C681*) alteration, located in exon 14 (coding exon 14) of the LDLR gene, consists of a C to A substitution at nucleotide position 2043. This changes the amino acid from a cysteine (C) to a stop codon at amino acid position 681. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration, also noted as p.C660X or the Lebanese allele, has been reported in individuals with familial hypercholesterolemia and a founder effect was proposed (Lehrman, 1987; Abifadel, 2009; Fahed, 2012). Based on the available evidence, this alteration is classified as pathogenic.
Comment:
ACMG categories: PVS1,PM2,PP1,PP5
Comment:
PVS1, PM2, PP5 - It's pathogenicity has already been established. ClinVar Variation ID 3699.
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. |
Comment:
subjects mutated among 2600 FH index cases screened = 31 (1 homozygote) , family members = 17 with co-segregation / FH-Libanon, < 2% LDLR Activity
Comment:
The c.2043C>A (p.Cys681*) variant in the LDLR gene has been reported in multiple individual patients with familial Hypercholesterolemia and segregated in the families (PMID: 3025214, 1959928, 1453433, 12406975, 22487947). This variant is extremely rare in general population and is predicted to introduce a premature translation termination codon. Therefore, the c.2043C>A (p.Cys681*) variant in the LDLR gene is classified as pathogenic.
Comment:
Criteria applied: PVS1,PS4,PM2_SUP,PP1
Comment:
This nonsense variant causes the premature termination of LDLR protein synthesis. The frequency of this variant in the general population, 0.000008 (2/251278 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported as a Lebanese founder mutation, but has also been identified in multiple other ethnic groups, in individuals and families with familial hypercholesterolemia (PMID: 28873201 (2017), 25461735 (2015), 22487947 (2012), 21145767 (2011), 19319977 (2009), 14974088 (2004), 11668627 (2001), 9664576 (1998), 3025214 (1987)). In a functional study, this variant was found to have a damaging effect on LDLR expression and binding (PMID: 31578082 (2019)). Based on the available information, this variant is classified as pathogenic.
Comment:
PP1, PS3, PS4_moderate, PVS1
Comment:
This sequence change creates a premature translational stop signal (p.Cys681*) 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 present in population databases (rs121908031, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 1959928, 11668627, 19319977, 21145767, 22487947, 25461735). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Cys660*. ClinVar contains an entry for this variant (Variation ID: 3699). For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant changes 1 nucleotide in exon 14 of the LDLR gene, creating a premature translation stop signal. This variant is also known as p.Cys660* in the mature protein. This variant is expected to result in an absent or non-functional protein product. Functional studies have shown that this variant causes a significant decrease in LDLR expression and LDL uptake (PMID: 31578082). This variant has been reported in over 100 individuals affected with familial hypercholesterolemia (PMID: 3025214, 11668627, 19319977, 21145767, 25461735, 28502510, 28761763, 28873201, 31578082, 34321884) and is considered to be a founder variant in the Lebanese population (PMID: 19319977). This variant has also been observed in both homozygous and compound heterozygous state with a known pathogenic LDLR variant in multiple individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 28761763, 31578082). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 19319977, 34321884). This variant has been identified in 2/251278 chromosomes 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.
Comment:
The p.Cys681X variant in LDLR has been reported in >80 individuals with hypercholesterolemia across several studies and segregated with disease in >10 affected relatives (Abifadel 2009, Banares 2017, Fahed 2011, Jannes 2015, Lehrman 1987, Tichy 2012, Vandrovcova 2013). This variant is considered to be a founder variant in the Lebanese population (Fahed 2016). This variant has also been reported in Clinvar (Variation ID 3699) and has been identified in 1/113666 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 681, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the LDLR gene is an established disease mechanism in familial hypercholesterolemia (FH). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant FH. ACMG/AMP criteria applied: PVS1, PS4, PM2, PP1_Strong.
Comment:
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; Reported many times in the heterozygous, compound heterozygous, and homozygous states in individuals with FH (PMID: 9664576, 9259195, 3025214, 10737984, 11668627, 12406975, 15200491, 28873201, 30179711); Considered a Lebanese founder mutation and may account for greater than 80% of FH cases in this population (PMID: 19319977); Published functional studies suggest a damaging effect on protein expression and binding (PMID: 31578082); Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.(C660X); This variant is associated with the following publications: (PMID: 31447099, 22487947, 25487149, 25525159, 3025214, 9259195, 9664576, 10737984, 11668627, 12406975, 15200491, 28873201, 30179711, 29407885, 34040191, 33303402, 34037665, 32041611, 33740630, 32770674, 33418990, 32231684, 35379577, 32009526, 33955087, 34321884, 15321837, 19319977, 37128917, 31578082)
Comment:
Variant summary: The LDLR c.2043C>A (p.Cys681X) variant results in a premature termination codon, predicted to cause a truncated or absent LDLR protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified in the pathogenic spectrum by our laboratory (e.g. p.Trp813X, p.Ser710fsX2 ). Mutation taster predicts a damaging outcome for this variant. This variant was found in 1/121136 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0025031). It was observed in several FH families and showed co-segregation with the disease indicating causality. Moreover, the variant was shown to result in lack of detectable high affinity binding and uptake of LDL, further supporting pathogenicity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
The nucleotide substitution c.2043C> A leads to a premature termination of protein synthesis at position 681 and is described as "FH Lebanese allele" in the literature. The mutation leads to intracellular degradation of the LDL receptor and loss of function. The mutation described here has also been described in patients with hypercholesterolemia and is therefore classified as pathogenic. PMID: 1453433, 3025214
Comment:
This variant changes 1 nucleotide in exon 14 of the LDLR gene, creating a premature translation stop signal. This variant is also known as p.Cys660* in the mature protein. This variant is expected to result in an absent or non-functional protein product. Functional studies have shown that this variant causes a significant decrease in LDLR expression and LDL uptake (PMID: 31578082). This variant has been reported in over 100 individuals affected with familial hypercholesterolemia (PMID: 3025214, 11668627, 19319977, 21145767, 25461735, 28502510, 28761763, 28873201, 31578082, 34321884) and is considered to be a founder variant in the Lebanese population (PMID: 19319977). This variant has also been observed in both homozygous and compound heterozygous state with a known pathogenic LDLR variant in multiple individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 28761763, 31578082). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 19319977, 34321884). This variant has been identified in 2/251278 chromosomes 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.
Comment:
The c.2043C>A (p.C681*) alteration, located in exon 14 (coding exon 14) of the LDLR gene, consists of a C to A substitution at nucleotide position 2043. This changes the amino acid from a cysteine (C) to a stop codon at amino acid position 681. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration, also noted as p.C660X or the Lebanese allele, has been reported in individuals with familial hypercholesterolemia and a founder effect was proposed (Lehrman, 1987; Abifadel, 2009; Fahed, 2012). Based on the available evidence, this alteration is classified as pathogenic.
Comment:
ACMG categories: PVS1,PM2,PP1,PP5
Comment:
PVS1, PM2, PP5 - It's pathogenicity has already been established. ClinVar Variation ID 3699.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Variable and Severe Phenotypic Expression of the "Lebanese Allele" in Two Sisters with Familial Hypercholesterolemia. | Chahine J | Vascular health and risk management | 2021 | PMID: 34321884 |
| A randomized controlled trial of genetic testing and cascade screening in familial hypercholesterolemia. | Ajufo E | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 34040191 |
| Limited-Variant Screening vs Comprehensive Genetic Testing for Familial Hypercholesterolemia Diagnosis. | Sturm AC | JAMA cardiology | 2021 | PMID: 34037665 |
| Cohort Generation and Characterization of Patient-Specific Familial Hypercholesterolemia Induced Pluripotent Stem Cells. | Omer L | Stem cells and development | 2021 | PMID: 34029164 |
| 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 LDLR, APOB, and PCSK9 Variants of Index Patients with Familial Hypercholesterolemia in Russia. | Meshkov A | Genes | 2021 | PMID: 33418990 |
| Combined hyperlipidemia is genetically similar to isolated hypertriglyceridemia. | Gill PK | Journal of clinical lipidology | 2021 | PMID: 33303402 |
| Mutation spectrum and polygenic score in German patients with familial hypercholesterolemia. | Rieck L | Clinical genetics | 2020 | PMID: 32770674 |
| Actionable Exomic Secondary Findings in 280 Lebanese Participants. | Jalkh N | Frontiers in genetics | 2020 | PMID: 32231684 |
| Functional Analysis of LDLR (Low-Density Lipoprotein Receptor) Variants in Patient Lymphocytes to Assess the Effect of Evinacumab in Homozygous Familial Hypercholesterolemia Patients With a Spectrum of LDLR Activity. | Banerjee P | Arteriosclerosis, thrombosis, and vascular biology | 2019 | PMID: 31578082 |
| 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 |
| Exome-Based Rare-Variant Analyses in CKD. | Cameron-Christie S | Journal of the American Society of Nephrology : JASN | 2019 | PMID: 31085678 |
| Diagnostic Utility of Exome Sequencing for Kidney Disease. | Groopman EE | The New England journal of medicine | 2019 | PMID: 30586318 |
| Corneal arcus as the presenting sign of familial hypercholesterolemia in a young child. | Lock JH | Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus | 2018 | PMID: 30179711 |
| Mutational screening in the LDLR gene among patients presenting familial hypercholesterolemia in the Southeast of Brazil. | Molfetta GA | Genetics and molecular research : GMR | 2017 | PMID: 28873201 |
| Premature Valvular Heart Disease in Homozygous Familial Hypercholesterolemia. | Fahed AC | Cholesterol | 2017 | PMID: 28761763 |
| Analysis of LDLR variants from homozygous FH patients carrying multiple mutations in the LDLR gene. | Jiang L | Atherosclerosis | 2017 | PMID: 28645073 |
| Preliminary spectrum of genetic variants in familial hypercholesterolemia in Argentina. | Bañares VG | Journal of clinical lipidology | 2017 | PMID: 28502510 |
| Clinical and molecular aspects of familial hypercholesterolemia in Ibero-American countries. | Santos RD | Journal of clinical lipidology | 2017 | PMID: 28391882 |
| Variable expressivity and co-occurrence of LDLR and LDLRAP1 mutations in familial hypercholesterolemia: failure of the dominant and recessive dichotomy. | Fahed AC | Molecular genetics & genomic medicine | 2016 | PMID: 27247956 |
| RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
| Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. | Do R | Nature | 2015 | PMID: 25487149 |
| Familial hypercholesterolemia in Brazil: cascade screening program, clinical and genetic aspects. | Jannes CE | Atherosclerosis | 2015 | PMID: 25461735 |
| The use of next-generation sequencing in clinical diagnosis of familial hypercholesterolemia. | Vandrovcova J | Genetics in medicine : official journal of the American College of Medical Genetics | 2013 | PMID: 23680767 |
| Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. | Bertolini S | Atherosclerosis | 2013 | PMID: 23375686 |
| The molecular basis of familial hypercholesterolemia in the Czech Republic: spectrum of LDLR mutations and genotype-phenotype correlations. | Tichý L | Atherosclerosis | 2012 | PMID: 22698793 |
| The Lebanese allele at the LDLR in normocholesterolemic people merits reconsideration of genotype phenotype correlations in familial hypercholesterolemia. | Fahed AC | Endocrine | 2012 | PMID: 22487947 |
| Homozygous familial hypercholesterolemia in Lebanon: a genotype/phenotype correlation. | Fahed AC | Molecular genetics and metabolism | 2011 | PMID: 21145767 |
| Molecular spectrum of autosomal dominant hypercholesterolemia in France. | Marduel M | Human mutation | 2010 | PMID: 20809525 |
| The molecular basis of familial hypercholesterolemia in Lebanon: spectrum of LDLR mutations and role of PCSK9 as a modifier gene. | Abifadel M | Human mutation | 2009 | PMID: 19319977 |
| Genetic diagnosis of familial hypercholesterolemia using a DNA-array based platform. | Alonso R | Clinical biochemistry | 2009 | PMID: 19318025 |
| Application of molecular genetics for diagnosing familial hypercholesterolemia in Norway: results from a family-based screening program. | Leren TP | Seminars in vascular medicine | 2004 | PMID: 15199436 |
| Molecular characterization of familial hypercholesterolemia in German and Greek patients. | Dedoussis GV | Human mutation | 2004 | PMID: 14974088 |
| Use of denaturing HPLC to provide efficient detection of mutations causing familial hypercholesterolemia. | Bodamer OA | Clinical chemistry | 2002 | PMID: 12406975 |
| 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 |
| Mutation analysis in familial hypercholesterolemia patients of different ancestries: identification of three novel LDLR gene mutations. | Callis M | Molecular and cellular probes | 1998 | PMID: 9664576 |
| Spectrum of LDL receptor gene mutations in heterozygous familial hypercholesterolemia. | Day IN | Human mutation | 1997 | PMID: 9259195 |
| High frequency of the Lebanese allele of the LDLr gene among Brazilian patients with familial hypercholesterolaemia. | Figueiredo MS | Journal of medical genetics | 1992 | PMID: 1453433 |
| Hypercholesterolemia in five Israeli Christian-Arab kindreds is caused by the "Lebanese" allele at the low density lipoprotein receptor gene locus and by an additional independent major factor. | Oppenheim A | Human genetics | 1991 | PMID: 1959928 |
| Duplication of seven exons in LDL receptor gene caused by Alu-Alu recombination in a subject with familial hypercholesterolemia. | Lehrman MA | Cell | 1987 | PMID: 3815525 |
| The Lebanese allele at the low density lipoprotein receptor locus. Nonsense mutation produces truncated receptor that is retained in endoplasmic reticulum. | Lehrman MA | The Journal of biological chemistry | 1987 | PMID: 3025214 |
| THE INHERITANCE OF ESSENTIAL FAMILIAL HYPERCHOLESTEROLEMIA. | KHACHADURIAN AK | The American journal of medicine | 1964 | PMID: 14209286 |
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Text-mined citations for this variant ...
HelpRecord last updated Nov 10, 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.