ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.502G>A (p.Asp168Asn)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000527.5(LDLR):c.502G>A (p.Asp168Asn)
Variation ID: 183136 Accession: VCV000183136.41
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11105408 (GRCh38) [ NCBI UCSC ] 19: 11216084 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Feb 28, 2015 May 1, 2024 Feb 20, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000527.5:c.502G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Asp168Asn missense NM_001195798.2:c.502G>A NP_001182727.1:p.Asp168Asn missense NM_001195799.2:c.379G>A NP_001182728.1:p.Asp127Asn missense NM_001195800.2:c.314-1984G>A intron variant NM_001195803.2:c.314-1157G>A intron variant NC_000019.10:g.11105408G>A NC_000019.9:g.11216084G>A NG_009060.1:g.21028G>A LRG_274:g.21028G>A LRG_274t1:c.502G>A LRG_274p1:p.Asp168Asn P01130:p.Asp168Asn - Protein change
- D168N, D127N
- Other names
- -
- Canonical SPDI
- NC_000019.10:11105407: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.
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
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 |
4017 | 4288 |
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 (2) |
criteria provided, single submitter
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Aug 10, 2022 | RCV000162017.6 | |
Pathogenic/Likely pathogenic (12) |
criteria provided, multiple submitters, no conflicts
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Dec 18, 2023 | RCV000211669.20 | |
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jan 7, 2024 | RCV000775041.14 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 7, 2021 | RCV000825592.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 20, 2024 | RCV002336377.2 | |
LDLR-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Nov 13, 2023 | RCV003927531.1 |
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. |
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Pathogenic
(Mar 10, 2019)
|
criteria provided, single submitter
Method: research
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Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
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Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia
Accession: SCV001432608.1
First in ClinVar: Sep 19, 2020 Last updated: Sep 19, 2020 |
Number of individuals with the variant: 1
Clinical Features:
Dutch Lipid Clinic Network Criteria score (present) , low-density lipoprotein cholesterol level (present)
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Pathogenic
(Aug 10, 2022)
|
criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV003762076.2
First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023 |
Comment:
Published functional studies demonstrate decreased receptor binding and LDL uptake compared to wild type protein (Etxebarria et al., 2015; Thormaehlen et al., 2015); Not observed … (more)
Published functional studies demonstrate decreased receptor binding and LDL uptake compared to wild type protein (Etxebarria et al., 2015; Thormaehlen et al., 2015); Not observed at a significant frequency in large population cohorts (gnomAD); Also known as D147N; This variant is associated with the following publications: (PMID: 9259195, 30617148, 15556094, 16205024, 31447099, 25487149, 9678702, 12124988, 19007590, 25647241, 22859806, 27784735, 29874871, 28379029, 23669246, 32522009, 33807407, 32853555, 32719484, 33740630, 34037665, 33087929, 2988123, 12459547, 25545329) (less)
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Likely pathogenic
(Mar 25, 2016)
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criteria provided, single submitter
Method: literature only
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Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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LDLR-LOVD, British Heart Foundation
Accession: SCV000294746.2
First in ClinVar: Jul 29, 2016 Last updated: Oct 10, 2018 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 1
Observation 3:
Number of individuals with the variant: 1
Observation 4:
Number of individuals with the variant: 1
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Likely pathogenic
(Dec 16, 2016)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
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Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix
Accession: SCV000503170.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Comment:
subjects mutated among 2600 FH index cases screened = 3 , family member = 1 with co-segregation / FH-Sephardic, 2 to 5% LDLR Activity / … (more)
subjects mutated among 2600 FH index cases screened = 3 , family member = 1 with co-segregation / FH-Sephardic, 2 to 5% LDLR Activity / Software predictions: Conflicting (less)
Number of individuals with the variant: 3
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Likely pathogenic
(Nov 05, 2016)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation
Additional submitter:
Centre of Molecular Biology and Gene Therapy, University Hospital Brno
Accession: SCV000540737.1
First in ClinVar: Apr 08, 2017 Last updated: Apr 08, 2017 |
Number of individuals with the variant: 1
Clinical Features:
Hypercholesterolemia (present) , Xanthelasma (present)
Family history: yes
Age: 40-49 years
Sex: female
Ethnicity/Population group: Caucasian
Geographic origin: Czech Republic
Tissue: Whole blood
Method: ADH Master kit (Multiplicom)
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Pathogenic
(Mar 01, 2016)
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criteria provided, single submitter
Method: research
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Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Fundacion Hipercolesterolemia Familiar
Study: SAFEHEART
Accession: SCV000607464.1 First in ClinVar: Apr 08, 2017 Last updated: Apr 08, 2017 |
Observation 1:
Comment on evidence:
%MAF(ExAC):0.001652
Observation 2:
Comment on evidence:
Heterologous cells (CHO), FACS assays
Result:
normal cell surface LDLR; 30-40% LDL-LDLR binding and uptake
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: research
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Familial hypercholesterolemia 1
Affected status: no
Allele origin:
germline
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UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill
Study: NSIGHT-NC NEXUS
Accession: SCV001251447.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
The LDLR c.502G>A (p.D168N) variant has been previously reported in the heterozygous state in autosomal dominant familial hypercholesterolemia (PMID: 9259195; 9678702; 12124988; 15556094; 19007590; 25545329; … (more)
The LDLR c.502G>A (p.D168N) variant has been previously reported in the heterozygous state in autosomal dominant familial hypercholesterolemia (PMID: 9259195; 9678702; 12124988; 15556094; 19007590; 25545329; 25647241). (less)
Number of individuals with the variant: 1
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Pathogenic
(Mar 02, 2020)
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criteria provided, single submitter
Method: clinical testing
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001339065.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: LDLR c.502G>A (p.Asp168Asn) results in a conservative amino acid change located in the LDLR ligand binding domain (R4) (Etxebarria_2015) of the encoded protein … (more)
Variant summary: LDLR c.502G>A (p.Asp168Asn) results in a conservative amino acid change located in the LDLR ligand binding domain (R4) (Etxebarria_2015) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251288 control chromosomes (gnomAD). c.502G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Taylor_2010, Rall_2014, Sanchez-Hernandez_2016, Wald-2016). These data indicate that the variant is very likely to be associated with disease. At least one functional study reports this variant effect results in an impaired LDL binding capacity of WT. Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (3x) and likely pathogenic (4x). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Aug 06, 2018)
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criteria provided, single submitter
Method: clinical testing
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
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Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV001434984.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
This c.502G>A (p.Asp168Asn) variant in the LDLR gene has been reported in multiple unrelated individuals with familial hypercholesterolemia (PMID 9259195, 15556094, 16205024, 19007590,22859806, 27784735) or … (more)
This c.502G>A (p.Asp168Asn) variant in the LDLR gene has been reported in multiple unrelated individuals with familial hypercholesterolemia (PMID 9259195, 15556094, 16205024, 19007590,22859806, 27784735) or myocardial infarction (PMID 25487149) and is extremely rare in general population. Functional studies have shown that this variant disrupts normal LDLR functionality by significantly decreasing LDL binding and LDL uptake (PMID 25545329). Based on this information, the c.502G>A (p.Asp168Asn) variant in the PCSK9 gene is classified as likely pathogenic. (less)
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Pathogenic
(Apr 07, 2021)
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criteria provided, single submitter
Method: clinical testing
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Homozygous familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000966934.2
First in ClinVar: Aug 26, 2019 Last updated: May 29, 2021 |
Comment:
The p.Asp168Asn variant in LDLR has been reported in the heterozygous state in at least 12 individuals (11 heterozygotes, 1 homozygote) with familial hypercholesterolemia (FH), … (more)
The p.Asp168Asn variant in LDLR has been reported in the heterozygous state in at least 12 individuals (11 heterozygotes, 1 homozygote) with familial hypercholesterolemia (FH), and in 2 individuals with early-onset myocardial infarction and segregated with FH in one affected relative (Day 1997 PMID: 9259195, Lee 1998 PMID: 9678702, Punzalan 2005 PMID: 16205024, Taylor 2010 PMID: 20236128, Do 2015 PMID: 25487149, Wald 2016 PMID: 27783906, Sanchez-Hernandez 2016 PMID: 27784735). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 183136) and has been identified in 0.002% (2/113632) European chromosomes by the gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that the p.Asp168Asn variant may cause a decrease in LDL uptake and binding (Etxebarria 2015 PMID: 25545329) and computational prediction tools and conservation analyses are consistent with pathogenicity. Additionally, other variants at this position (p.Asp168His, p.Asp168Gly, p.Asp168Gln) have been reported in association with FH by multiple clinical laboratories in ClinVar. In summary, the p.Asp168Asn variant meets criteria to be classified as pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PS4, PS3_Moderate, PM1, PM2_Supporting, PP3, PM5_Supporting. (less)
Number of individuals with the variant: 3
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Pathogenic
(Aug 24, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
maternal
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001950090.1
First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(Dec 06, 2021)
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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: SCV002777075.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Dec 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003827850.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Mar 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000909138.3
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant (also known as p.Asp147Asn in the mature protein) replaces aspartic acid with asparagine at codon 168 in the fourth LDLR type A … (more)
This missense variant (also known as p.Asp147Asn in the mature protein) replaces aspartic acid with asparagine at codon 168 in the fourth LDLR type A repeat of the ligand binding domain of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant causes a significant decrease in LDL binding and uptake, although effect is not as severe as null alleles (PMID: 25545329, 25647241). This variant has been reported in over ten individuals and families affected with familial hypercholesterolemia (PMID: 15556094, 16205024, 16389549, 17955342, 22859806, 23669246, 27784735, 28379029, 33807407, 34037665; Color internal data), including a homozygous individual with severe phenotype (PMID: 27784735). This variant has been identified in 2/251288 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same amino acid position (p.Asp168His, p.Asp168Gly, p.Asp168Tyr) are known to be disease-causing (ClinVar variation ID: 251258, 251260, 251259), indicating that aspartic acid at this position is important for LDLR function. Based on available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Jan 07, 2024)
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criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000627039.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 168 of the LDLR protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 168 of the LDLR protein (p.Asp168Asn). This variant is present in population databases (rs200727689, gnomAD 0.002%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9259195, 9678702, 12124988, 15556094, 16205024, 19007590, 22859806, 27784735). This variant is also known as p.Asp147Asn. ClinVar contains an entry for this variant (Variation ID: 183136). 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: 25545329, 25647241). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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LDLR-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004744631.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The LDLR c.502G>A variant is predicted to result in the amino acid substitution p.Asp168Asn. This variant is alternatively referred to as p.Asp147Asn using Legacy nomenclature. … (more)
The LDLR c.502G>A variant is predicted to result in the amino acid substitution p.Asp168Asn. This variant is alternatively referred to as p.Asp147Asn using Legacy nomenclature. This variant and other similar variants affecting amino acid Asp168 have been reported in several unrelated patients with hypercholesterolemia (Day et al. 1997 PubMed ID: 9259195; Lee et al. 1998 PubMed ID: 9678702; Punzalan et al. 2005 PubMed ID: 16205024; Civiera et al. 2008 PubMed ID: 19007590; Etxebarria et al. 2015 PubMed ID: 25545329). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-11216084-G-A) and is reported as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/183136/). This variant is interpreted as pathogenic. (less)
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Pathogenic
(Dec 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
(Semidominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004820173.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This missense variant (also known as p.Asp147Asn in the mature protein) replaces aspartic acid with asparagine at codon 168 in the fourth LDLR type A … (more)
This missense variant (also known as p.Asp147Asn in the mature protein) replaces aspartic acid with asparagine at codon 168 in the fourth LDLR type A repeat of the ligand binding domain of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant causes a significant decrease in LDL binding and uptake, although effect is not as severe as null alleles (PMID: 25545329, 25647241). This variant has been reported in over ten individuals and families affected with familial hypercholesterolemia (PMID: 15556094, 16205024, 16389549, 17955342, 22859806, 23669246, 27784735, 28379029, 33807407, 34037665; Color internal data), including a homozygous individual with severe phenotype (PMID: 27784735). This variant has been identified in 2/251288 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same amino acid position (p.Asp168His, p.Asp168Gly, p.Asp168Tyr) are known to be disease-causing (ClinVar variation ID: 251258, 251260, 251259), indicating that aspartic acid at this position is important for LDLR function. Based on available evidence, this variant is classified as Pathogenic. (less)
Number of individuals with the variant: 5
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Likely pathogenic
(Feb 20, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002642995.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.D168N variant (also known as c.502G>A), located in coding exon 4 of the LDLR gene, results from a G to A substitution at nucleotide … (more)
The p.D168N variant (also known as c.502G>A), located in coding exon 4 of the LDLR gene, results from a G to A substitution at nucleotide position 502. The aspartic acid at codon 168 is replaced by asparagine, an amino acid with highly similar properties, and is located in the ligand binding region of the protein. This alteration (also referred to as D147N) has been detected in individuals from multiple familial hypercholesterolemia cohorts and in an an individual with mixed hyperlipidemia (Day IN et al. Hum Mutat. 1997;10:116-27; Lee WK et al. J Med Genet. 1998;35:573-8; Laurie AD et al. Atheroscler Suppl. 2004;5(5):13-5;Civeira F et al. J Am Coll Cardiol. 2008; Futema M et al. Atherosclerosis. 2013;229:161-8; Raal FJ et al. Lancet. 2015;385(9965):341-50; Sánchez-Hernández RM et al. Circ Cardiovasc Genet. 2016;9(6):504-510). This variant has been reported to result in reduced LDL binding and uptake in vitro (Etxebarria A et al. Atherosclerosis. 2015 Feb;238(2):304-12; Thormaehlen AS et al. PLoS Genet. 2015;11(2):e1004855). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Pathogenic
(Feb 11, 2020)
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no assertion criteria provided
Method: clinical testing
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002086367.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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Pathogenic
(Oct 09, 2023)
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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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Zotz-Klimas Genetics Lab, MVZ Zotz Klimas
Accession: SCV004041738.1
First in ClinVar: Oct 14, 2023 Last updated: Oct 14, 2023 |
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Pathogenic
(Apr 04, 2014)
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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: SCV000268566.1
First in ClinVar: May 21, 2016 Last updated: May 21, 2016 |
Number of individuals with the variant: 1
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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: SCV000189620.1
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
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The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
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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
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A brief description of the result of this method for this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting 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: SCV000189620.1
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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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Limited-Variant Screening vs Comprehensive Genetic Testing for Familial Hypercholesterolemia Diagnosis. | Sturm AC | JAMA cardiology | 2021 | PMID: 34037665 |
Molecular Genetic Approach and Evaluation of Cardiovascular Events in Patients with Clinical Familial Hypercholesterolemia Phenotype from Romania. | Vlad CE | Journal of clinical medicine | 2021 | PMID: 33807407 |
Molecular genetic background of an autosomal dominant hypercholesterolemia in the Czech Republic. | Tichý L | Physiological research | 2017 | PMID: 28379029 |
The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. | Stenson PD | Human genetics | 2017 | PMID: 28349240 |
Low-density lipoprotein receptor mutational analysis in diagnosis of familial hypercholesterolemia. | Bourbon M | Current opinion in lipidology | 2017 | PMID: 28169869 |
Homozygous Familial Hypercholesterolemia in Spain: Prevalence and Phenotype-Genotype Relationship. | Sánchez-Hernández RM | Circulation. Cardiovascular genetics | 2016 | PMID: 27784735 |
Child-Parent Familial Hypercholesterolemia Screening in Primary Care. | Wald DS | The New England journal of medicine | 2016 | PMID: 27783906 |
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 |
Activity-associated effect of LDL receptor missense variants located in the cysteine-rich repeats. | Etxebarria A | Atherosclerosis | 2015 | PMID: 25545329 |
Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. | Do R | Nature | 2015 | PMID: 25487149 |
Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. | Raal FJ | Lancet (London, England) | 2015 | PMID: 25282520 |
Analysis of the frequency and spectrum of mutations recognised to cause familial hypercholesterolaemia in routine clinical practice in a UK specialist hospital lipid clinic. | Futema M | Atherosclerosis | 2013 | PMID: 23669246 |
Genetic mutations in patients with possible familial hypercholesterolaemia in South East Scotland. | Ho CK | Scottish medical journal | 2012 | PMID: 22859806 |
Mutation detection rate and spectrum in familial hypercholesterolaemia patients in the UK pilot cascade project. | Taylor A | Clinical genetics | 2010 | PMID: 20236128 |
Frequency of low-density lipoprotein receptor gene mutations in patients with a clinical diagnosis of familial combined hyperlipidemia in a clinical setting. | Civeira F | Journal of the American College of Cardiology | 2008 | PMID: 19007590 |
Hyperlipoproteinaemia(a) is a common cause of autosomal dominant hypercholesterolaemia. | Meriño-Ibarra E | Journal of inherited metabolic disease | 2007 | PMID: 17955342 |
Mutational analysis in UK patients with a clinical diagnosis of familial hypercholesterolaemia: relationship with plasma lipid traits, heart disease risk and utility in relative tracing. | Humphries SE | Journal of molecular medicine (Berlin, Germany) | 2006 | PMID: 16389549 |
Low density lipoprotein--receptor (LDL-R) gene mutations among Filipinos with familial hypercholesterolemia. | Punzalan FE | Journal of atherosclerosis and thrombosis | 2005 | PMID: 16205024 |
Genetic screening of patients with familial hypercholesterolaemia (FH): a New Zealand perspective. | Laurie AD | Atherosclerosis. Supplements | 2004 | PMID: 15556094 |
The UMD-LDLR database: additions to the software and 490 new entries to the database. | Villéger L | Human mutation | 2002 | PMID: 12124988 |
Identification of a common low density lipoprotein receptor mutation (C163Y) in the west of Scotland. | Lee WK | Journal of medical genetics | 1998 | PMID: 9678702 |
Spectrum of LDL receptor gene mutations in heterozygous familial hypercholesterolemia. | Day IN | Human mutation | 1997 | PMID: 9259195 |
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Text-mined citations for rs200727689 ...
HelpRecord last updated May 19, 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.