The NM_000527.5(LDLR):c.1765G>A (p.Asp589Asn) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: BP4 - REVEL = 0.325. It is below 0.5, splicing evaluation needed. Functional data on splicing not available. A) variant not on limits. B) does not create AG or GT Variant is not predicted to alter splicing
ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.1765G>A (p.Asp589Asn)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Uncertain significance
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000527.5(LDLR):c.1765G>A (p.Asp589Asn)
Variation ID: 252022 Accession: VCV000252022.24
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19p13.2 19: 11116918 (GRCh38) [ NCBI UCSC ] 19: 11227594 (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 Jul 29, 2016 Sep 16, 2024 Aug 29, 2022 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.1765G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Asp589Asn missense NM_001195798.2:c.1765G>A NP_001182727.1:p.Asp589Asn missense NM_001195799.2:c.1642G>A NP_001182728.1:p.Asp548Asn missense NM_001195800.2:c.1261G>A NP_001182729.1:p.Asp421Asn missense NM_001195803.2:c.1384G>A NP_001182732.1:p.Asp462Asn missense NC_000019.10:g.11116918G>A NC_000019.9:g.11227594G>A NG_009060.1:g.32538G>A LRG_274:g.32538G>A LRG_274t1:c.1765G>A LRG_274p1:p.Asp589Asn - Protein change
- D589N, D421N, D462N, D548N
- Other names
-
NM_000527.5(LDLR):c.1765G>A
- Canonical SPDI
- NC_000019.10:11116917:G: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.
-
0.00060 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
1000 Genomes Project 0.00060
- 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 |
4075 | 4351 | |
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. |
|---|---|---|---|---|
| Uncertain significance (8) |
reviewed by expert panel
|
Aug 29, 2022 | RCV000237292.11 | |
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 1, 2023 | RCV000775077.11 | |
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Dec 4, 2023 | RCV000845536.5 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Apr 11, 2024 | RCV002401946.4 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jun 18, 2024 | RCV003155136.2 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Aug 29, 2022)
|
reviewed by expert panel
Method: curation
|
Hypercholesterolemia, familial, 1
(Semidominant inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV002817142.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
The NM_000527.5(LDLR):c.1765G>A (p.Asp589Asn) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes BP4 as defined by the ClinGen … (more)
The NM_000527.5(LDLR):c.1765G>A (p.Asp589Asn) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: BP4 - REVEL = 0.325. It is below 0.5, splicing evaluation needed. Functional data on splicing not available. A) variant not on limits. B) does not create AG or GT Variant is not predicted to alter splicing (less)
|
|
|
Uncertain significance
(Mar 25, 2016)
|
criteria provided, single submitter
Method: literature only
|
Familial hypercholesterolemia
Affected status: yes
Allele origin:
germline
|
LDLR-LOVD, British Heart Foundation
Accession: SCV000295644.2
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
|
|
|
Uncertain significance
(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: SCV000503409.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Comment:
subjects mutated among 2600 FH index cases screened = 2 / in association with c.769C>T, p.Arg257Trp/Software predictions: Benign
Number of individuals with the variant: 2
|
|
|
Uncertain significance
(Oct 09, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000544660.6
First in ClinVar: Apr 16, 2017 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 589 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 589 of the LDLR protein (p.Asp589Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 16250003, 20538126, 22353362, 25962062, 26343872, 27206935, 28502495, 29353225, 29399563, 34040191). This variant is also known as p.Asp568Asn. ClinVar contains an entry for this variant (Variation ID: 252022). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
|
Uncertain significance
(Jan 02, 2018)
|
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: SCV000782927.1
First in ClinVar: May 30, 2018 Last updated: May 30, 2018 |
|
|
|
Uncertain significance
(-)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000987650.1
First in ClinVar: Sep 08, 2019 Last updated: Sep 08, 2019 |
|
|
|
Uncertain significance
(May 13, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002047050.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
|
|
|
Uncertain significance
(Feb 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002814931.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Uncertain significance
(Mar 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000909179.5
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant (also known as p.Asp568Asn in the mature protein) replaces aspartic acid with asparagine at codon 589 of the LDLR protein. Computational prediction … (more)
This missense variant (also known as p.Asp568Asn in the mature protein) replaces aspartic acid with asparagine at codon 589 of the LDLR protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant has been reported in several individuals affected with familial hypercholesterolemia in Korea, Taiwan, China and the Netherlands (PMID: 16250003, 25962062, 22353362, 20538126, 26343872, 30795984, 32629184, 32759540, 33994402, 34456200). It has also been reported in an individual affected with metabolic syndrome (PMID: 35999587). This variant has also been identified in 18/246268 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
|
|
|
Uncertain Significance
(Dec 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
(Semidominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004822499.1
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)
|
Comment:
This missense variant (also known as p.Asp568Asn in the mature protein) replaces aspartic acid with asparagine at codon 589 of the LDLR protein. Computational prediction … (more)
This missense variant (also known as p.Asp568Asn in the mature protein) replaces aspartic acid with asparagine at codon 589 of the LDLR protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <=0.5, PMID: 27666373). This variant has been reported in several individuals affected with familial hypercholesterolemia in Korea, Taiwan, China and the Netherlands (PMID: 16250003, 25962062, 22353362, 20538126, 26343872, 30795984, 32629184, 32759540, 33994402, 34456200). It has also been reported in an individual affected with metabolic syndrome (PMID: 35999587). This variant has also been identified in 18/246268 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 6
|
|
|
Uncertain significance
(Apr 11, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002710616.4
First in ClinVar: Nov 29, 2022 Last updated: Aug 11, 2024 |
Comment:
The p.D589N variant (also known as c.1765G>A), located in coding exon 12 of the LDLR gene, results from a G to A substitution at nucleotide … (more)
The p.D589N variant (also known as c.1765G>A), located in coding exon 12 of the LDLR gene, results from a G to A substitution at nucleotide position 1765. The aspartic acid at codon 589 is replaced by asparagine, an amino acid with highly similar properties. This alteration (also referred to as p.D568N) has been reported in several familial hypercholesterolemia (FH) cohorts and is reported to occur with p.R257W on the same allele in some instances (Fouchier SW et al. Hum. Mutat., 2005 Dec;26:550-6; Chiou KR et al. Am. J. Cardiol., 2010 Jun;105:1752-8; Chiou KR et al. Gene, 2012 Apr;498:100-6; Shin DG et al. Atherosclerosis, 2015 Nov;243:53-8; Pek SLT et al. Atherosclerosis, 2018 Feb;269:106-116). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. (less)
|
|
|
Uncertain significance
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Cardiology Department, Cho Ray Hospital
Additional submitter:
Genesolutions, Medical Genetics Institutes, Ho Chi Minh City, Vietnam
Accession: SCV005186231.1
First in ClinVar: Aug 18, 2024 Last updated: Aug 18, 2024 |
Comment:
The 35-year-old male patient was admitted with a high LDL-C level of 435 mg/dL and a confirmed diagnosis of triple vessel coronary artery disease. Medical … (more)
The 35-year-old male patient was admitted with a high LDL-C level of 435 mg/dL and a confirmed diagnosis of triple vessel coronary artery disease. Medical history: dyslipidemia, myocardial infarction at age 34. Family history: Biological father died of a myocardial infarction at the age of 45. Genetic diagnosis: homozygote variants of LDLR c.1765G>A (p.Asp589Asn). (less)
Age: 30-39 years
Sex: male
Ethnicity/Population group: Kinh
Geographic origin: Vietnam
|
|
|
Uncertain significance
(Dec 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV005201893.1
First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
Comment:
Observed in multiple unrelated patients from different ethnic backgrounds with familial hypercholesterolemia (FH) in the published literature (PMID: 18325082, 16250003, 20538126, 25962062, 26343872, 29353225, 30526649, … (more)
Observed in multiple unrelated patients from different ethnic backgrounds with familial hypercholesterolemia (FH) in the published literature (PMID: 18325082, 16250003, 20538126, 25962062, 26343872, 29353225, 30526649, 30592178, 30795984); Many individuals with p.(D589N) in the published literature harbor a second variant in LDLR (p.R257W) in cis, including two individuals homozygous for both variants (PMID: 25962062, 20538126, 34456200); these variants are suspected to be linked on the same allele; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(D568N); This variant is associated with the following publications: (PMID: 26332594, 29353225, 30526649, 30592178, 30795984, 22353362, 27206935, 26343872, 16250003, 29399563, 32629184, 20538126, 28502495, 34040191, 33740630, 35538921, 33994402, 32759540, 35999587, 34456200, 25962062, 18325082, 30400955) (less)
|
|
|
Uncertain significance
(Jun 18, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003844389.2
First in ClinVar: Mar 26, 2023 Last updated: Sep 16, 2024 |
Comment:
Variant summary: LDLR c.1765G>A (p.Asp589Asn) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign … (more)
Variant summary: LDLR c.1765G>A (p.Asp589Asn) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 251490 control chromosomes, predominantly at a frequency of 0.0011 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (8.4e-05 vs 0.0013), allowing no conclusion about variant significance. c.1765G>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia without strong evidence for causality, and often found along with c.769C>T (e.g. Chiou_2010, Chiou_2017, Sun_2018, Chan_2018, Huang_2022). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20538126, 30592178, 28502495, 30400955, 33994402). ClinVar contains an entry for this variant (Variation ID: 252022). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum
Accession: SCV000606508.1
First in ClinVar: Apr 16, 2017 Last updated: Apr 16, 2017 |
|
|
|
Uncertain significance
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001461317.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Comment:
Comment:
subjects mutated among 2600 FH index cases screened = 2 / in association with c.769C>T, p.Arg257Trp/Software predictions: Benign
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 589 of the LDLR protein (p.Asp589Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 16250003, 20538126, 22353362, 25962062, 26343872, 27206935, 28502495, 29353225, 29399563, 34040191). This variant is also known as p.Asp568Asn. ClinVar contains an entry for this variant (Variation ID: 252022). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
This missense variant (also known as p.Asp568Asn in the mature protein) replaces aspartic acid with asparagine at codon 589 of the LDLR protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant has been reported in several individuals affected with familial hypercholesterolemia in Korea, Taiwan, China and the Netherlands (PMID: 16250003, 25962062, 22353362, 20538126, 26343872, 30795984, 32629184, 32759540, 33994402, 34456200). It has also been reported in an individual affected with metabolic syndrome (PMID: 35999587). This variant has also been identified in 18/246268 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
This missense variant (also known as p.Asp568Asn in the mature protein) replaces aspartic acid with asparagine at codon 589 of the LDLR protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <=0.5, PMID: 27666373). This variant has been reported in several individuals affected with familial hypercholesterolemia in Korea, Taiwan, China and the Netherlands (PMID: 16250003, 25962062, 22353362, 20538126, 26343872, 30795984, 32629184, 32759540, 33994402, 34456200). It has also been reported in an individual affected with metabolic syndrome (PMID: 35999587). This variant has also been identified in 18/246268 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The p.D589N variant (also known as c.1765G>A), located in coding exon 12 of the LDLR gene, results from a G to A substitution at nucleotide position 1765. The aspartic acid at codon 589 is replaced by asparagine, an amino acid with highly similar properties. This alteration (also referred to as p.D568N) has been reported in several familial hypercholesterolemia (FH) cohorts and is reported to occur with p.R257W on the same allele in some instances (Fouchier SW et al. Hum. Mutat., 2005 Dec;26:550-6; Chiou KR et al. Am. J. Cardiol., 2010 Jun;105:1752-8; Chiou KR et al. Gene, 2012 Apr;498:100-6; Shin DG et al. Atherosclerosis, 2015 Nov;243:53-8; Pek SLT et al. Atherosclerosis, 2018 Feb;269:106-116). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Comment:
The 35-year-old male patient was admitted with a high LDL-C level of 435 mg/dL and a confirmed diagnosis of triple vessel coronary artery disease. Medical history: dyslipidemia, myocardial infarction at age 34. Family history: Biological father died of a myocardial infarction at the age of 45. Genetic diagnosis: homozygote variants of LDLR c.1765G>A (p.Asp589Asn).
Comment:
Observed in multiple unrelated patients from different ethnic backgrounds with familial hypercholesterolemia (FH) in the published literature (PMID: 18325082, 16250003, 20538126, 25962062, 26343872, 29353225, 30526649, 30592178, 30795984); Many individuals with p.(D589N) in the published literature harbor a second variant in LDLR (p.R257W) in cis, including two individuals homozygous for both variants (PMID: 25962062, 20538126, 34456200); these variants are suspected to be linked on the same allele; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(D568N); This variant is associated with the following publications: (PMID: 26332594, 29353225, 30526649, 30592178, 30795984, 22353362, 27206935, 26343872, 16250003, 29399563, 32629184, 20538126, 28502495, 34040191, 33740630, 35538921, 33994402, 32759540, 35999587, 34456200, 25962062, 18325082, 30400955)
Comment:
Variant summary: LDLR c.1765G>A (p.Asp589Asn) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 251490 control chromosomes, predominantly at a frequency of 0.0011 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (8.4e-05 vs 0.0013), allowing no conclusion about variant significance. c.1765G>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia without strong evidence for causality, and often found along with c.769C>T (e.g. Chiou_2010, Chiou_2017, Sun_2018, Chan_2018, Huang_2022). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20538126, 30592178, 28502495, 30400955, 33994402). ClinVar contains an entry for this variant (Variation ID: 252022). Based on the evidence outlined above, the variant was classified as uncertain significance.
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:
The NM_000527.5(LDLR):c.1765G>A (p.Asp589Asn) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: BP4 - REVEL = 0.325. It is below 0.5, splicing evaluation needed. Functional data on splicing not available. A) variant not on limits. B) does not create AG or GT Variant is not predicted to alter splicing
Comment:
subjects mutated among 2600 FH index cases screened = 2 / in association with c.769C>T, p.Arg257Trp/Software predictions: Benign
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 589 of the LDLR protein (p.Asp589Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 16250003, 20538126, 22353362, 25962062, 26343872, 27206935, 28502495, 29353225, 29399563, 34040191). This variant is also known as p.Asp568Asn. ClinVar contains an entry for this variant (Variation ID: 252022). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
This missense variant (also known as p.Asp568Asn in the mature protein) replaces aspartic acid with asparagine at codon 589 of the LDLR protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant has been reported in several individuals affected with familial hypercholesterolemia in Korea, Taiwan, China and the Netherlands (PMID: 16250003, 25962062, 22353362, 20538126, 26343872, 30795984, 32629184, 32759540, 33994402, 34456200). It has also been reported in an individual affected with metabolic syndrome (PMID: 35999587). This variant has also been identified in 18/246268 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
This missense variant (also known as p.Asp568Asn in the mature protein) replaces aspartic acid with asparagine at codon 589 of the LDLR protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <=0.5, PMID: 27666373). This variant has been reported in several individuals affected with familial hypercholesterolemia in Korea, Taiwan, China and the Netherlands (PMID: 16250003, 25962062, 22353362, 20538126, 26343872, 30795984, 32629184, 32759540, 33994402, 34456200). It has also been reported in an individual affected with metabolic syndrome (PMID: 35999587). This variant has also been identified in 18/246268 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The p.D589N variant (also known as c.1765G>A), located in coding exon 12 of the LDLR gene, results from a G to A substitution at nucleotide position 1765. The aspartic acid at codon 589 is replaced by asparagine, an amino acid with highly similar properties. This alteration (also referred to as p.D568N) has been reported in several familial hypercholesterolemia (FH) cohorts and is reported to occur with p.R257W on the same allele in some instances (Fouchier SW et al. Hum. Mutat., 2005 Dec;26:550-6; Chiou KR et al. Am. J. Cardiol., 2010 Jun;105:1752-8; Chiou KR et al. Gene, 2012 Apr;498:100-6; Shin DG et al. Atherosclerosis, 2015 Nov;243:53-8; Pek SLT et al. Atherosclerosis, 2018 Feb;269:106-116). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Comment:
The 35-year-old male patient was admitted with a high LDL-C level of 435 mg/dL and a confirmed diagnosis of triple vessel coronary artery disease. Medical history: dyslipidemia, myocardial infarction at age 34. Family history: Biological father died of a myocardial infarction at the age of 45. Genetic diagnosis: homozygote variants of LDLR c.1765G>A (p.Asp589Asn).
Comment:
Observed in multiple unrelated patients from different ethnic backgrounds with familial hypercholesterolemia (FH) in the published literature (PMID: 18325082, 16250003, 20538126, 25962062, 26343872, 29353225, 30526649, 30592178, 30795984); Many individuals with p.(D589N) in the published literature harbor a second variant in LDLR (p.R257W) in cis, including two individuals homozygous for both variants (PMID: 25962062, 20538126, 34456200); these variants are suspected to be linked on the same allele; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(D568N); This variant is associated with the following publications: (PMID: 26332594, 29353225, 30526649, 30592178, 30795984, 22353362, 27206935, 26343872, 16250003, 29399563, 32629184, 20538126, 28502495, 34040191, 33740630, 35538921, 33994402, 32759540, 35999587, 34456200, 25962062, 18325082, 30400955)
Comment:
Variant summary: LDLR c.1765G>A (p.Asp589Asn) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 251490 control chromosomes, predominantly at a frequency of 0.0011 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (8.4e-05 vs 0.0013), allowing no conclusion about variant significance. c.1765G>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia without strong evidence for causality, and often found along with c.769C>T (e.g. Chiou_2010, Chiou_2017, Sun_2018, Chan_2018, Huang_2022). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20538126, 30592178, 28502495, 30400955, 33994402). ClinVar contains an entry for this variant (Variation ID: 252022). Based on the evidence outlined above, the variant was classified as uncertain significance.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Identification of genetic variants related to metabolic syndrome by next-generation sequencing. | Lee S | Diabetology & metabolic syndrome | 2022 | PMID: 35999587 |
| Phenotypic and Genetic Analyses of Korean Patients with Familial Hypercholesterolemia: Results from the KFH Registry 2020. | Kim H | Journal of atherosclerosis and thrombosis | 2022 | PMID: 34456200 |
| Genetic Analysis in a Taiwanese Cohort of 750 Index Patients with Clinically Diagnosed Familial Hypercholesterolemia. | Huang CC | Journal of atherosclerosis and thrombosis | 2022 | PMID: 33994402 |
| 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 |
| 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 |
| Targeted Genetic Analysis in a Chinese Cohort of 208 Patients Related to Familial Hypercholesterolemia. | Wang H | Journal of atherosclerosis and thrombosis | 2020 | PMID: 32759540 |
| A systematic review of LDLR, PCSK9, and APOB variants in Asia. | Mahdieh N | Atherosclerosis | 2020 | PMID: 32629184 |
| The clinical and molecular diversity of homozygous familial hypercholesterolemia in children: Results from the GeneTics of clinical homozygous hypercholesterolemia (GoTCHA) study. | Luirink IK | Journal of clinical lipidology | 2019 | PMID: 30795984 |
| Genetic variations in familial hypercholesterolemia and cascade screening in East Asians. | Chan ML | Molecular genetics & genomic medicine | 2019 | PMID: 30592178 |
| Application of expanded genetic analysis in the diagnosis of familial hypercholesterolemia in patients with very early-onset coronary artery disease. | Cao YX | Journal of translational medicine | 2018 | PMID: 30526649 |
| Genetic basis of index patients with familial hypercholesterolemia in Chinese population: mutation spectrum and genotype-phenotype correlation. | Sun D | Lipids in health and disease | 2018 | PMID: 30400955 |
| Identification of a novel LDLR disease-causing variant using capture-based next-generation sequencing screening of familial hypercholesterolemia patients in Taiwan. | Hsiung YC | Atherosclerosis | 2018 | PMID: 30270083 |
| Detection of Familial Hypercholesterolemia Using Next Generation Sequencing in Two Population-Based Cohorts. | Kim HN | Chonnam medical journal | 2018 | PMID: 29399563 |
| Spectrum of mutations in index patients with familial hypercholesterolemia in Singapore: Single center study. | Pek SLT | Atherosclerosis | 2018 | PMID: 29353225 |
| Detection of common sequence variations of familial hypercholesterolemia in Taiwan using DNA mass spectrometry. | Chiou KR | Journal of clinical lipidology | 2017 | PMID: 28502495 |
| Genetic diagnosis of familial hypercholesterolemia in Han Chinese. | Chiou KR | Journal of clinical lipidology | 2016 | PMID: 27206935 |
| Clinical features of familial hypercholesterolemia in Korea: Predictors of pathogenic mutations and coronary artery disease - A study supported by the Korean Society of Lipidology and Atherosclerosis. | Shin DG | Atherosclerosis | 2015 | PMID: 26343872 |
| Identification of Medically Actionable Secondary Findings in the 1000 Genomes. | Olfson E | PloS one | 2015 | PMID: 26332594 |
| Genetic testing of Korean familial hypercholesterolemia using whole-exome sequencing. | Han SM | PloS one | 2015 | PMID: 25962062 |
| Common mutations of familial hypercholesterolemia patients in Taiwan: characteristics and implications of migrations from southeast China. | Chiou KR | Gene | 2012 | PMID: 22353362 |
| Detection of mutations and large rearrangements of the low-density lipoprotein receptor gene in Taiwanese patients with familial hypercholesterolemia. | Chiou KR | The American journal of cardiology | 2010 | PMID: 20538126 |
| Update and analysis of the University College London low density lipoprotein receptor familial hypercholesterolemia database. | Leigh SE | Annals of human genetics | 2008 | PMID: 18325082 |
| Update of the molecular basis of familial hypercholesterolemia in The Netherlands. | Fouchier SW | Human mutation | 2005 | PMID: 16250003 |
| 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 |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/fd0cb6c9-7f1e-4644-9c34-95083a79a553 | - | - | - | - |
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Text-mined citations for rs201971888 ...
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Record last updated Sep 29, 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.