ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.1646G>A (p.Gly549Asp)
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
-
NM_000527.5(LDLR):c.1646G>A (p.Gly549Asp)
Variation ID: 3698 Accession: VCV000003698.52
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11116153 (GRCh38) [ NCBI UCSC ] 19: 11226829 (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 Feb 28, 2015 Oct 13, 2024 Aug 21, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000527.5:c.1646G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Gly549Asp missense NM_001195798.2:c.1646G>A NP_001182727.1:p.Gly549Asp missense NM_001195799.2:c.1523G>A NP_001182728.1:p.Gly508Asp missense NM_001195800.2:c.1142G>A NP_001182729.1:p.Gly381Asp missense NM_001195803.2:c.1265G>A NP_001182732.1:p.Gly422Asp missense NC_000019.10:g.11116153G>A NC_000019.9:g.11226829G>A NG_009060.1:g.31773G>A LRG_274:g.31773G>A LRG_274t1:c.1646G>A LRG_274p1:p.Gly549Asp P01130:p.Gly549Asp - Protein change
- G549D, G508D, G381D, G422D
- Other names
- G528D
- FH Genoa
- FH Palermo-1
- NP_000518.1:p.G549D
- Canonical SPDI
- NC_000019.10:11116152:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- functional variant Sequence Ontology [SO:0001536]
- disruptive missense [submitted by Dept. of Genetics and Pharmacogenomics, Merck Research Labs]
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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
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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LDLR | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
4070 | 4346 |
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 (20) |
criteria provided, multiple submitters, no conflicts
|
Aug 21, 2024 | RCV000003886.32 | |
Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Jan 2, 2024 | RCV000161997.27 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jan 17, 2024 | RCV000587938.15 | |
Pathogenic (1) |
criteria provided, single submitter
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May 2, 2022 | RCV002390088.3 |
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
(-)
|
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: SCV000484682.1
First in ClinVar: Dec 17, 2016 Last updated: Dec 17, 2016 |
Number of individuals with the variant: 2
|
|
Likely 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: SCV000503381.1
First in ClinVar: Dec 17, 2016 Last updated: Dec 17, 2016 |
Comment:
subjects mutated among 2600 FH index cases screened = 4 , family member = 1 with co-segregation / FH-Palermo, 2% LDLR activity / Software predictions: … (more)
subjects mutated among 2600 FH index cases screened = 4 , family member = 1 with co-segregation / FH-Palermo, 2% LDLR activity / Software predictions: Damaging (less)
Number of individuals with the variant: 4
|
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Likely pathogenic
(Nov 05, 2016)
|
criteria provided, single submitter
Method: clinical testing
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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: SCV000540828.1
First in ClinVar: Apr 08, 2017 Last updated: Apr 08, 2017 |
Number of individuals with the variant: 1
Clinical Features:
Hypercholesterolemia (present)
Age: 0-9 years
Sex: male
Ethnicity/Population group: Caucasian
Geographic origin: Czech Republic
Tissue: Whole blood
Method: ADH Master kit (Multiplicom)
|
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Likely 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: SCV000588600.1 First in ClinVar: Aug 13, 2017 Last updated: Aug 13, 2017 |
Observation 1:
Comment on evidence:
%MAF(ExAC):0.004944
Observation 2:
Comment on evidence:
Assay description:Hmz patient fibroblast, 125I-LDL assays / Htz patients' Epstein-Barr virus transformed lymphocytes, FACS assays
Result:
<2% / 45-65% LDLR activity
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Pathogenic
(Mar 17, 2017)
|
criteria provided, single submitter
Method: clinical testing
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697207.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
|
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000894176.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
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Pathogenic
(Dec 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002046853.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
Comment:
In the published literature, this variant has been reported in individuals affected with familial hypercholesterolemia (FH) (PMIDs: 9259195 (1997), 9544850 (1998), 9974426 (1999), 11317361 (2001), … (more)
In the published literature, this variant has been reported in individuals affected with familial hypercholesterolemia (FH) (PMIDs: 9259195 (1997), 9544850 (1998), 9974426 (1999), 11317361 (2001), 12436241 (2002), 15199436 (2004), 15241806 (2004), 19837725 (2010), 22371747 (2010), and 23375686 (2013)). In addition, functional analyses report that this variant results in decreased LDLR protein activity, with <2% residual activity in homozygous individuals and a mean residual activity of 50% in heterozygous individuals (PMID: 1301956 (1992), 21865347 (2011), and 25647241 (2015)). Therefore, the variant is classified as pathogenic. (less)
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Pathogenic
(May 09, 2022)
|
criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004175360.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
|
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Pathogenic
(Feb 15, 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
|
Revvity Omics, Revvity
Accession: SCV002017106.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
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Pathogenic
(Jan 05, 2024)
|
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: SCV004822484.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This missense variant replaces glycine with aspartic acid at codon 549 of the LDLR protein. This variant is also known as p.Gly528Asp in the mature … (more)
This missense variant replaces glycine with aspartic acid at codon 549 of the LDLR protein. This variant is also known as p.Gly528Asp in the mature protein and as FH Genoa and FH Palermo-1 in the literature. This variant alters a conserved glycine residue in the fourth LDLR type B repeat of the EGF precursor homology domain of the LDLR protein (a.a. 529 - 572), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction tool suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). High throughput assays and functional studies with heterologous cells and homozygous patient fibroblasts have shown that this variant results in defective LDL transport/uptake and retains <2% LDLR activity compared to wild type (PMID: 1301956, 25647241, 31106925). Heterozygous patient cells showed 35-65% LDLR activity compared to wild type (PMID: 21865347). This variant has been reported in over 100 individuals affected with familial hypercholesterolemia (PMID: 1301956, 9259195, 9544850, 11810272, 15241806, 21865347, 22371747, 23375686, 31106925) and is particularly common in Greek (PMID: 8683740) and Italian populations (PMID: 23375686). This variant has been identified in 6/246260 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic. (less)
Number of individuals with the variant: 4
|
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Pathogenic
(Sep 04, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848439.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Gly549Asp variant in LDLR has been reported in many individuals with familial hypercholesterolemia and has been shown to segregate in >10 affected family members … (more)
The p.Gly549Asp variant in LDLR has been reported in many individuals with familial hypercholesterolemia and has been shown to segregate in >10 affected family members (Marino 1999 PMID:10338098, Dedoussis 2004 PMID:14974088, Diakou 2010 PMID:22371747, Bertolini 2013 PMID:23375686, Thormaehlen 2015 PMID:25647241, Benito-Vicente 2018 PMID:29874871). This variant is known as a common pathogenic variant in the Italian population, and is referred to as FH Genoa and p.Gly528Asp in the literature. It has been reported in ClinVar (Variation ID 3698). An in vitro functional study indicates that this variant is associated with abnormal transport of LDL receptor protein in which the receptor mislocalizes endoplasmatic reticulum (ER)-like membranes (Benito-Vicente 2018 PMID:29874871). This variant has been identified in 0.005% (6/113752) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, for diseases with clinical variability or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant familial hypercholesterolemia. ACMG/AMP criteria applied: PS4, PP1_Strong, PP3, PS3_Supporting. (less)
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Pathogenic
(Jan 02, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005198658.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
Likely pathogenic
(Mar 25, 2016)
|
criteria provided, single submitter
Method: literature only
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Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
LDLR-LOVD, British Heart Foundation
Accession: SCV000295560.2
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
|
|
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: SCV000583858.1
First in ClinVar: Apr 16, 2017 Last updated: Apr 16, 2017
Comment:
ACMG Guidelines: Pathogenic (ii)
|
Number of individuals with the variant: 11
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
|
|
Likely 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: SCV000607619.1 First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
Observation 1:
Comment on evidence:
%MAF(ExAC):0.004944
Observation 2:
Comment on evidence:
Hmz patient fibroblast, 125I-LDL assays / Htz patients' Epstein-Barr virus transformed lymphocytes, FACS assays
Result:
<2% / 45-65% LDLR activity
|
|
Pathogenic
(Feb 11, 2020)
|
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: SCV001433282.1
First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020 |
|
|
Pathogenic
(Aug 06, 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: SCV001435010.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
The c.1646G>A (p.Gly549Asp) variant has been reported in multiple unrelated patients with familial hypercholesterolemia (PMID 1301956,9259195, 9544850, 11810272, 15199436, 15241806, 19837725, 21865347, 23375686) or myocardial … (more)
The c.1646G>A (p.Gly549Asp) variant has been reported in multiple unrelated patients with familial hypercholesterolemia (PMID 1301956,9259195, 9544850, 11810272, 15199436, 15241806, 19837725, 21865347, 23375686) or myocardial infarction (PMID 25487149). A functional study reported the mutant LDLR protein retains less than 2 percent receptor activity compared to wild type LDLR protein (PMID 1301956) and the variant is classified as 'disruptive' through systematic cell-based phenotyping (PMID 25647241). Therefore, this c.1646G>A (p.Gly549Asp) variant is classified as pathogenic. (less)
|
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Pathogenic
(May 24, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
|
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II
Accession: SCV001653643.1
First in ClinVar: Jun 08, 2021 Last updated: Jun 08, 2021 |
Comment:
Reduced activity, in stimulated T-lymphocytes and EBV-transformed B-lymphocytes.
Number of individuals with the variant: 29
Ethnicity/Population group: Caucasian
Geographic origin: Italy
|
|
Pathogenic
(Jul 02, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001715493.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Number of individuals with the variant: 1
|
|
Pathogenic
(Dec 30, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001782225.3
First in ClinVar: Aug 14, 2021 Last updated: Mar 04, 2023 |
Comment:
Also reported as FH Genoa, FH Palermo-1, and G528D due to alternate nomenclature; Published functional studies demonstrate a damaging effect with abnormal LDL transport/uptake and … (more)
Also reported as FH Genoa, FH Palermo-1, and G528D due to alternate nomenclature; Published functional studies demonstrate a damaging effect with abnormal LDL transport/uptake and significantly reduced receptor activity (Hobbs et al., 1990; Romano et al., 2011; Thormaehlen et al., 2015; Rodriguez-Jimenez et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar (ClinVar Variant ID#3698; ClinVar); This variant is associated with the following publications: (PMID: 21925044, 29874871, 28965616, 33093846, 23375686, 25487149, 25647241, 25525159, 21865347, 28391899, 20045108, 2088165, 9259195, 9544850, 11317361, 15199436, 15241806, 19446849, 19717150, 19837725, 22371747, 21310417, 25463123, 27578104, 31447099, 31106925, 34040191, 32977124, 32041611, 32770674, 33740630, 34037665) (less)
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Pathogenic
(Oct 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV004013975.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
PS3, PM1, PM5, PP2, PP3, PP5
|
|
Pathogenic
(Jan 17, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000544685.10
First in ClinVar: Apr 16, 2017 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 549 of the LDLR protein … (more)
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 549 of the LDLR protein (p.Gly549Asp). This variant is present in population databases (rs28941776, gnomAD 0.005%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 23375686, 25487149). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Italian ancestry (PMID: 23375686, 25487149). This variant is also known as p.Glu528Asp. ClinVar contains an entry for this variant (Variation ID: 3698). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects LDLR function (PMID: 25647241). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Sep 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001346737.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces glycine with aspartic acid at codon 549 of the LDLR protein. This variant is also known as p.Gly528Asp in the mature … (more)
This missense variant replaces glycine with aspartic acid at codon 549 of the LDLR protein. This variant is also known as p.Gly528Asp in the mature protein and as FH Genoa and FH Palermo-1 in the literature. This variant alters a conserved glycine residue in the fourth LDLR type B repeat of the EGF precursor homology domain of the LDLR protein (a.a. 529 - 572), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction tool suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). High throughput assays and functional studies with heterologous cells and homozygous patient fibroblasts have shown that this variant results in defective LDL transport/uptake and retains <2% LDLR activity compared to wild type (PMID: 1301956, 25647241, 31106925). Heterozygous patient cells showed 35-65% LDLR activity compared to wild type (PMID: 21865347). This variant has been reported in over 100 individuals affected with familial hypercholesterolemia (PMID: 1301956, 9259195, 9544850, 11810272, 15241806, 21865347, 22371747, 23375686, 31106925) and is particularly common in Greek (PMID: 8683740) and Italian populations (PMID: 23375686). This variant has been identified in 6/246260 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic. (less)
|
|
Pathogenic
(May 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002704025.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.G549D pathogenic mutation (also known as c.1646G>A), located in coding exon 11 of the LDLR gene, results from a G to A substitution at … (more)
The p.G549D pathogenic mutation (also known as c.1646G>A), located in coding exon 11 of the LDLR gene, results from a G to A substitution at nucleotide position 1646. The glycine at codon 549 is replaced by aspartic acid, an amino acid with similar properties. This alteration, also referred to as p.G528D, has been shown to reduce LDLR activity to 35-65% of normal levels in vitro (Romano M et al. J Lipid Res. 2011;52(11):2095-100) and prevent LDLR endocytosis (Thormaehlen AS et al. PLoS Genet. 2015;11(2): e1004855). In addition, this mutation has been found to be a common pathogenic alteration in various familial hypercholesterolemia population cohorts (Traeger-Synodinos J et al. Hum Genet. 1998, Diakou M et al, Arch Med Sci 2010; 6(2):198-200, Bertolini S et al, Atherosclerosis 2013;227(2):342-8; Pirillo A et al. Atheroscler Suppl, 2017 Oct;29:17-24), possibly stemming from a common ancestor (Bertolini S et al. Arterioscler Thromb Vasc Biol. 2000;20(9):E41-52). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Mar 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV003918064.12
First in ClinVar: Apr 23, 2023 Last updated: Oct 08, 2024 |
Comment:
LDLR: PM1:Strong, PM5, PS3:Moderate, PS4:Moderate
Number of individuals with the variant: 1
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Pathogenic
(Aug 21, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV005368412.1
First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024 |
Comment:
Criteria applied: PS4,PM5_STR,PM2,PP3
Clinical Features:
Increased LDL cholesterol concentration (present)
Sex: male
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Pathogenic
(Nov 01, 1988)
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no assertion criteria provided
Method: literature only
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FH GENOA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000024051.2
First in ClinVar: Apr 04, 2013 Last updated: Dec 01, 2017 |
Comment on evidence:
A GGT-to-GAT mutation is responsible for this variant (Leitersdorf and Hobbs, 1990).
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Pathogenic
(Aug 25, 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: SCV002086430.1
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: SCV000606474.1
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: SCV000733824.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
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Likely pathogenic
(Mar 01, 2016)
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no assertion criteria provided
Method: research
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Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Iberoamerican FH Network
Accession: SCV000748175.1
First in ClinVar: May 19, 2018 Last updated: May 19, 2018
Comment:
Variant present in the database from Chile
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Observation 1:
Comment on evidence:
%MAF(ExAC):0.004944
Observation 2:
Comment on evidence:
Assay Description:Hmz patient fibroblast, 125I-LDL assays / Htz patients' Epstein-Barr virus transformed lymphocytes, FACS assays
Result:
<2% / 45-65% LDLR activity
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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: SCV001925125.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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not provided
(-)
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no classification provided
(in vitro)
Method: in vitro
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not provided
Affected status: not applicable
Allele origin:
not applicable
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Dept. of Genetics and Pharmacogenomics, Merck Research Labs
Accession: SCV000189572.1
First in ClinVar: Feb 28, 2015 Last updated: Feb 28, 2015
Comment:
In vitro functional profiling of LDL-receptor missense alleles identified through large-scale association testing
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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has functional consequence
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Dept. of Genetics and Pharmacogenomics, Merck Research Labs
Accession: SCV000189572.1
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Comment:
disruptive missense
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Homozygous familial hypercholesterolemia in Italy: Clinical and molecular features. | Bertolini S | Atherosclerosis | 2020 | PMID: 32977124 |
Mutation spectrum and polygenic score in German patients with familial hypercholesterolemia. | Rieck L | Clinical genetics | 2020 | PMID: 32770674 |
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 |
Functional analysis of new variants at the low-density lipoprotein receptor associated with familial hypercholesterolemia. | Rodríguez-Jiménez C | Human mutation | 2019 | PMID: 31106925 |
Lipid profile and genetic status in a familial hypercholesterolemia pediatric population: exploring the LDL/HDL ratio. | Di Taranto MD | Clinical chemistry and laboratory medicine | 2019 | PMID: 30710474 |
Validation of LDLr Activity as a Tool to Improve Genetic Diagnosis of Familial Hypercholesterolemia: A Retrospective on Functional Characterization of LDLr Variants. | Benito-Vicente A | International journal of molecular sciences | 2018 | PMID: 29874871 |
Spectrum of mutations in Italian patients with familial hypercholesterolemia: New results from the LIPIGEN study. | Pirillo A | Atherosclerosis. Supplements | 2017 | PMID: 28965616 |
Analysis of Children and Adolescents with Familial Hypercholesterolemia. | Minicocci I | The Journal of pediatrics | 2017 | PMID: 28161202 |
Genetic causes of monogenic familial hypercholesterolemia in the Greek population: Lessons, mistakes, and the way forward. | Mollaki V | Journal of clinical lipidology | 2016 | PMID: 27578104 |
Systematic cell-based phenotyping of missense alleles empowers rare variant association studies: a case for LDLR and myocardial infarction. | Thormaehlen AS | PLoS genetics | 2015 | PMID: 25647241 |
Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. | Do R | Nature | 2015 | PMID: 25487149 |
Presence and type of low density lipoprotein receptor (LDLR) mutation influences the lipid profile and response to lipid-lowering therapy in Brazilian patients with heterozygous familial hypercholesterolemia. | Santos PC | Atherosclerosis | 2014 | PMID: 24529145 |
Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. | Bertolini S | Atherosclerosis | 2013 | PMID: 23375686 |
An improved method on stimulated T-lymphocytes to functionally characterize novel and known LDLR mutations. | Romano M | Journal of lipid research | 2011 | PMID: 21865347 |
Characterization of low density lipoprotein receptor (LDLR) gene mutations in Albania. | Diakou M | Archives of medical science : AMS | 2010 | PMID: 22371747 |
Development of a high-resolution melting method for mutation detection in familial hypercholesterolaemia patients. | Whittall RA | Annals of clinical biochemistry | 2010 | PMID: 19837725 |
Impact of low-density lipoprotein receptor mutational class on carotid atherosclerosis in patients with familial hypercholesterolemia. | Junyent M | Atherosclerosis | 2010 | PMID: 19717150 |
Molecular characterization of familial hypercholesterolemia in Spain: identification of 39 novel and 77 recurrent mutations in LDLR. | Mozas P | Human mutation | 2004 | PMID: 15241806 |
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 |
Intronic mutations outside of Alu-repeat-rich domains of the LDL receptor gene are a cause of familial hypercholesterolemia. | Amsellem S | Human genetics | 2002 | PMID: 12436241 |
The molecular basis of familial hypercholesterolemia in The Netherlands. | Fouchier SW | Human genetics | 2001 | PMID: 11810272 |
Characterization and geographic distribution of the low density lipoprotein receptor (LDLR) gene mutations in northwestern Greece. | Miltiadous G | Human mutation | 2001 | PMID: 11317361 |
Clinical expression of familial hypercholesterolemia in clusters of mutations of the LDL receptor gene that cause a receptor-defective or receptor-negative phenotype. | Bertolini S | Arteriosclerosis, thrombosis, and vascular biology | 2000 | PMID: 10978268 |
Rapid screening of the LDL receptor point mutation FH-Genoa/Palermo. Mutation in brief no. 238. Online. | Marino G | Human mutation | 1999 | PMID: 10338098 |
Analysis of LDL receptor gene mutations in Italian patients with homozygous familial hypercholesterolemia. | Bertolini S | Arteriosclerosis, thrombosis, and vascular biology | 1999 | PMID: 9974426 |
Analysis of low density lipoprotein receptor gene mutations and microsatellite haplotypes in Greek FH heterozygous children: six independent ancestors account for 60% of probands. | Traeger-Synodinos J | Human genetics | 1998 | PMID: 9544850 |
Spectrum of LDL receptor gene mutations in heterozygous familial hypercholesterolemia. | Day IN | Human mutation | 1997 | PMID: 9259195 |
Angiotensin II and basic fibroblast growth factor induce neonatal bladder stromal cell mitogenesis. | Cheng EY | The Journal of urology | 1996 | PMID: 8683740 |
Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. | Hobbs HH | Human mutation | 1992 | PMID: 1301956 |
The LDL receptor locus in familial hypercholesterolemia: mutational analysis of a membrane protein. | Hobbs HH | Annual review of genetics | 1990 | PMID: 2088165 |
Deletion in the first cysteine-rich repeat of low density lipoprotein receptor impairs its transport but not lipoprotein binding in fibroblasts from a subject with familial hypercholesterolemia. | Leitersdorf E | Proceedings of the National Academy of Sciences of the United States of America | 1988 | PMID: 3263645 |
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Text-mined citations for this variant ...
HelpRecord last updated Oct 13, 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.