ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.2120A>T (p.Asp707Val)
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.2120A>T (p.Asp707Val)
Variation ID: 252227 Accession: VCV000252227.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11120502 (GRCh38) [ NCBI UCSC ] 19: 11231178 (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 Dec 17, 2016 Aug 11, 2024 May 30, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000527.5:c.2120A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Asp707Val missense NM_001195798.2:c.2120A>T NP_001182727.1:p.Asp707Val missense NM_001195799.2:c.1997A>T NP_001182728.1:p.Asp666Val missense NM_001195800.2:c.1616A>T NP_001182729.1:p.Asp539Val missense NM_001195803.2:c.1606+269A>T intron variant NC_000019.10:g.11120502A>T NC_000019.9:g.11231178A>T NG_009060.1:g.36122A>T LRG_274:g.36122A>T LRG_274t1:c.2120A>T LRG_274p1:p.Asp707Val - Protein change
- D707V, D666V, D539V
- Other names
- NP_000518.1:p.D707V
- Canonical SPDI
- NC_000019.10:11120501:A:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Dec 16, 2016 | RCV000237572.11 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 8, 2017 | RCV000521276.8 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 30, 2024 | RCV004639196.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 30, 2019 | RCV001258046.8 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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
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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
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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 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
(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: SCV000295882.2
First in ClinVar: Jul 29, 2016 Last updated: Dec 17, 2016 |
Number of individuals with the variant: 1
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Robarts Research Institute, Western University
Accession: SCV000484742.1
First in ClinVar: Dec 17, 2016 Last updated: Dec 17, 2016 |
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: SCV000503465.1
First in ClinVar: Dec 17, 2016 Last updated: Dec 17, 2016 |
Comment:
subject mutated among 2600 FH index cases screened = 1 , family member = 1 with co-segregation/software prediction damaging
Number of individuals with the variant: 1
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Likely pathogenic
(Sep 08, 2017)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000617512.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
Comment:
A variant that is likely pathogenic was identified in the LDLR gene. The D707V variant has been reported in association with FH (Marduel et al., … (more)
A variant that is likely pathogenic was identified in the LDLR gene. The D707V variant has been reported in association with FH (Marduel et al., 2010; Wang et al., 2016). The D707V variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D707V variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Finally, while missense variants in the same residue (D707N, D707Y) have been reported in the Human Gene Mutation Database in association with FH (Stenson et al., 2014), the pathogenicity of these variants has not been definitively determined. (less)
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Likely pathogenic
(Oct 30, 2019)
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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: SCV001434875.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
The c.2120A>T (p.Asp707Val) variant in the LDLR gene has been reported in individuals with familial hypercholesterolemia (FH) (PMID: 20809525, 27765764) and is absent from general … (more)
The c.2120A>T (p.Asp707Val) variant in the LDLR gene has been reported in individuals with familial hypercholesterolemia (FH) (PMID: 20809525, 27765764) and is absent from general population databases. Multiple lines of in silico algorithms have predicted this p.Asp707Val change to be deleterious. In addition, missense variants in the same amino acid residue (p.Asp707Asn and p.Asp707Tyr) have also been reported in affected individuals with FH (PMID: 22881376, 19318025). Therefore, this c.2120A>T (p.Asp707Val) variant in the LDLR gene is classified as likely pathogenic. (less)
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Likely pathogenic
(May 30, 2024)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV005135991.1
First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
Comment:
The p.D707V variant (also known as c.2120A>T), located in coding exon 14 of the LDLR gene, results from an A to T substitution at nucleotide … (more)
The p.D707V variant (also known as c.2120A>T), located in coding exon 14 of the LDLR gene, results from an A to T substitution at nucleotide position 2120. The aspartic acid at codon 707 is replaced by valine, an amino acid with highly dissimilar properties. This variant has been reported in individuals with familial hypercholesterolemia (FH) (Marduel M et al. Hum Mutat, 2010 Nov;31:E1811-24; Wang J et al. Arterioscler Thromb Vasc Biol, 2016 Dec;36:2439-2445; Björnsson E et al. Arterioscler Thromb Vasc Biol, 2021 Oct;41:2616-2628). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Likely pathogenic
(Jul 21, 2023)
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no assertion criteria provided
Method: research
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Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
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deCODE genetics, Amgen
Accession: SCV004022250.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
The variant NM_000527.5:c.2120A>T (chr19:11120502) in LDLR was detected in 3 heterozygotes out of 58K WGS Icelanders (MAF= 0,003%). Following imputation in a set of 166K … (more)
The variant NM_000527.5:c.2120A>T (chr19:11120502) in LDLR was detected in 3 heterozygotes out of 58K WGS Icelanders (MAF= 0,003%). Following imputation in a set of 166K Icelanders (4 imputed heterozygotes) we observed an association with LDL cholesterol using measurements from 128289 individuals (Effect (SD)= 2.53, P= 8.17e-06), Non-HDL cholesterol using measurements from 136901 individuals (Effect (SD)= 2.31, P= 3.79e-05), pure hypercholesterolaemia using 1515 cases and 283197 controls (OR= 84.06, P= 3.36e-04) and myocardial infarction using 25692 cases and 320832 controls (OR= 56.16, P= 1.36e-03). This variant has been reported in ClinVar previously as likely pathogenic. Based on ACMG criteria (PS4, PM1, PP3, PP5_Strong) this variant classifies as likely pathogenic. (less)
Number of individuals with the variant: 4
Ethnicity/Population group: Icelandic
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Large-Scale Screening for Monogenic and Clinically Defined Familial Hypercholesterolemia in Iceland. | Björnsson E | Arteriosclerosis, thrombosis, and vascular biology | 2021 | PMID: 34407635 |
Polygenic Versus Monogenic Causes of Hypercholesterolemia Ascertained Clinically. | Wang J | Arteriosclerosis, thrombosis, and vascular biology | 2016 | PMID: 27765764 |
Molecular spectrum of autosomal dominant hypercholesterolemia in France. | Marduel M | Human mutation | 2010 | PMID: 20809525 |
Text-mined citations for rs879255143 ...
HelpRecord last updated Sep 01, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.