ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.1951G>A (p.Asp651Asn)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000527.5(LDLR):c.1951G>A (p.Asp651Asn)
Variation ID: 183128 Accession: VCV000183128.36
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11120197 (GRCh38) [ NCBI UCSC ] 19: 11230873 (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 Aug 4, 2024 Mar 20, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000527.5:c.1951G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Asp651Asn missense NM_001195798.2:c.1951G>A NP_001182727.1:p.Asp651Asn missense NM_001195799.2:c.1828G>A NP_001182728.1:p.Asp610Asn missense NM_001195800.2:c.1447G>A NP_001182729.1:p.Asp483Asn missense NM_001195803.2:c.1570G>A NP_001182732.1:p.Asp524Asn missense NC_000019.10:g.11120197G>A NC_000019.9:g.11230873G>A NG_009060.1:g.35817G>A LRG_274:g.35817G>A LRG_274t1:c.1951G>A LRG_274p1:p.Asp651Asn - Protein change
- D651N, D610N, D483N, D524N
- Other names
- NM_000527.5(LDLR):c.1951G>A
- Canonical SPDI
- NC_000019.10:11120196:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- no known functional consequence
- non-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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
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
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 |
4059 | 4334 |
Conditions - Germline
Condition
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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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Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 1, 2024 | RCV000162005.17 | |
Likely pathogenic (7) |
reviewed by expert panel
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Mar 20, 2023 | RCV000238255.8 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Nov 27, 2023 | RCV000590648.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 10, 2023 | RCV002415706.3 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Mar 20, 2023)
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reviewed by expert panel
Method: curation
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Hypercholesterolemia, familial, 1
(Semidominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV004022455.1 First in ClinVar: Aug 05, 2023 Last updated: Aug 05, 2023 |
Comment:
The NM_000527.5(LDLR):c.1951G>A (p.Asp651Asn) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PS4_Moderate, PM2, PP1, and PP4 as defined by the … (more)
The NM_000527.5(LDLR):c.1951G>A (p.Asp651Asn) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PS4_Moderate, PM2, PP1, and PP4 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: PS4_Moderate: Variant meets PM2 and is identified in 8 unrelated index cases (1 case with Simon-Broome criteria of possible FH and 1 case with Simon-Broome criteria of definite FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), 2 cases with Simon-Broome criteria of possible FH and 1 case with DLCN>6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, and 3 cases in PMID 15241806 (Mozas P et al., 2004)). So PS4_Moderate is met. PM2: PopMax MAF = 0.00001 (0.001%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1). So PM2 is met. PP1: Variant segregates with FH phenotype in 3 informative meioses identified by Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies. So PP1 is met. PP4: Variant meets PM2 and is identified in2 unrelated index cases who fulfill clinical criteria for FH (see PS4 for details). So PP4 is met. (less)
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Uncertain significance
(Mar 25, 2016)
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criteria provided, single submitter
Method: literature only
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Familial hypercholesterolemia
Affected status: yes
Allele origin:
germline
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LDLR-LOVD, British Heart Foundation
Accession: SCV000295769.2
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Number of individuals with the variant: 1
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Pathogenic
(Nov 27, 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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Invitae
Accession: SCV001221619.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 651 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 651 of the LDLR protein (p.Asp651Asn). This variant is present in population databases (rs730882110, gnomAD 0.0009%). This missense change has been observed in individuals with autosomal dominant and autosomal recessive LDLR-related conditions (PMID: 15241806, 25487149, 29396260, 30312929; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as p.D630N. ClinVar contains an entry for this variant (Variation ID: 183128). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on LDLR function (PMID: 25647241). This variant disrupts the p.Asp651 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 16389549, 19318025), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Dec 11, 2023)
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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: SCV005078485.1
First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as D630N; This variant is associated with the following publications: (PMID: 15241806, 25647241, 29396260, 30312929, 25487149) (less)
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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: SCV000503436.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Comment:
subject mutated among 2600 FH index cases screened = 1 , family members = 3 with co-segregation / previously described in association with FH/Software predictions: … (more)
subject mutated among 2600 FH index cases screened = 1 , family members = 3 with co-segregation / previously described in association with FH/Software predictions: Conflicting (less)
Number of individuals with the variant: 1
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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:
inherited
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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: SCV000540849.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Number of individuals with the variant: 2
Clinical Features:
Hypercholesterolemia (present)
Age: 20-29 years
Sex: female
Ethnicity/Population group: Caucasian
Geographic origin: Czech Republic
Tissue: Whole blood
Method: ADH Master kit (Multiplicom)
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Uncertain significance
(Mar 01, 2016)
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criteria provided, single submitter
Method: research
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
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Fundacion Hipercolesterolemia Familiar
Study: SAFEHEART
Accession: SCV000607657.1 First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Comment on evidence:
%MAF(ExAC):0.0008237
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Likely pathogenic
(May 19, 2016)
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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: SCV000697217.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The LDLR c.1951G>A (p.Asp651Asn) variant involves the alteration of a conserved nucleotide and is located in 'precursor homology' domain. 3/4 in silico tools … (more)
Variant summary: The LDLR c.1951G>A (p.Asp651Asn) variant involves the alteration of a conserved nucleotide and is located in 'precursor homology' domain. 3/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). This variant was found in 1/131578 control chromosomes at a frequency of 0.0000076, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). This variant has been found in three apparently non-related FH patients (Mozas_2004) as well as in one patient with myocardial infarction (Do_2015). Other missense changes at this codon such as Asp651Tyr has also been detected in FH patients, suggesting that the codon may be a mutational hot-spot. Taken together, it variant has been classified as a Probable Disease Variant (or likely pathogenic). (less)
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Likely pathogenic
(Mar 22, 2022)
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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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3billion
Accession: SCV002318907.1
First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported to be associated with LDLR related disorder (PMID:15241806). A different missense change … (more)
Same nucleotide change resulting in same amino acid change has been previously reported to be associated with LDLR related disorder (PMID:15241806). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000252127,VCV000252128, PMID:16389549,19318025). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.697>=0.6, 3CNET: 0.97>=0.75). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Hypercholesterolemia (present)
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Likely pathogenic
(Apr 28, 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: SCV001352604.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant (also known as p.Asp630Asn in the mature protein) replaces aspartic acid with asparagine at codon 651 in the LDLR type B repeat … (more)
This missense variant (also known as p.Asp630Asn in the mature protein) replaces aspartic acid with asparagine at codon 651 in the LDLR type B repeat 6 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A high-throughput functional study has shown that this variant may not cause a significant impact to LDL uptake (PMID: 25647241). This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 15241806, 15890894, 30312929; ClinVar SCV000540849.1, SCV002318907.1, SCV000503436.1, SCV001221619.4; Color internal data). It has also been reported in an individual affected with early-onset myocardial infarction (PMID: 25487149). This variant has also been observed in compound heterozygous state in an individual affected with homozygous familial hypercholesterolemia (PMID: 29396260), indicating that this variant contributes to disease. This variant has been identified in 1/251464 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
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Likely Pathogenic
(Aug 08, 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
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All of Us Research Program, National Institutes of Health
Accession: SCV004818472.1
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.Asp630Asn in the mature protein) replaces aspartic acid with asparagine at codon 651 in the LDLR type B repeat … (more)
This missense variant (also known as p.Asp630Asn in the mature protein) replaces aspartic acid with asparagine at codon 651 in the LDLR type B repeat 6 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A high-throughput functional study has shown that this variant may not cause a significant impact to LDL uptake (PMID: 25647241). This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 15241806, 15890894, 30312929; ClinVar SCV000540849.1, SCV002318907.1, SCV000503436.1, SCV001221619.4; Color internal data). It has also been reported in an individual affected with early-onset myocardial infarction (PMID: 25487149). This variant has also been observed in compound heterozygous state in an individual affected with homozygous familial hypercholesterolemia (PMID: 29396260), indicating that this variant contributes to disease. This variant has been identified in 1/251464 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Feb 10, 2023)
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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: SCV002718288.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.D651N variant (also known as c.1951G>A), located in coding exon 13 of the LDLR gene, results from a G to A substitution at nucleotide … (more)
The p.D651N variant (also known as c.1951G>A), located in coding exon 13 of the LDLR gene, results from a G to A substitution at nucleotide position 1951. The aspartic acid at codon 651 is replaced by asparagine, an amino acid with highly similar properties. This alteration, which is also known as p.D630N, was reported in a Spanish familial hypercholesterolemia (FH) cohort, and was found by exome sequencing in individuals with myocardial infarction; however, clinical details were limited (Mozas P et al. Hum Mutat. 2004;24:187; Do R et al. Nature. 2015;518:102-6; Thormaehlen AS et al. PLoS Genet. 2015;11:e1004855). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Likely pathogenic
(Jan 01, 2024)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001151670.17
First in ClinVar: Feb 03, 2020 Last updated: Aug 04, 2024 |
Comment:
LDLR: PM2, PM5, PS4:Moderate
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: SCV000189580.1
First in ClinVar: Feb 28, 2015 Last updated: Feb 28, 2015
Comment:
In vitro functional profiling of LDL-receptor missense alleles identified through large-scale association testing
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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no known functional consequence
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Dept. of Genetics and Pharmacogenomics, Merck Research Labs
Accession: SCV000189580.1
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Comment:
non-disruptive missense
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Detecting familial hypercholesterolemia earlier in life by actively searching for affected children:The DECOPIN project. | Ibarretxe D | Atherosclerosis | 2018 | PMID: 30312929 |
Alirocumab efficacy in patients with double heterozygous, compound heterozygous, or homozygous familial hypercholesterolemia. | Hartgers ML | Journal of clinical lipidology | 2018 | PMID: 29396260 |
Systematic cell-based phenotyping of missense alleles empowers rare variant association studies: a case for LDLR and myocardial infarction. | Thormaehlen AS | PLoS genetics | 2015 | PMID: 25647241 |
Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. | Do R | Nature | 2015 | PMID: 25487149 |
Genetic diagnosis of familial hypercholesterolemia using a DNA-array based platform. | Alonso R | Clinical biochemistry | 2009 | PMID: 19318025 |
Complement regulation in murine and human hypercholesterolemia and role in the control of macrophage and smooth muscle cell proliferation. | Verdeguer F | Cardiovascular research | 2007 | PMID: 17673191 |
Analysis of sequence variations in the LDL receptor gene in Spain: general gene screening or search for specific alterations? | Blesa S | Clinical chemistry | 2006 | PMID: 16627557 |
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 |
Reliable low-density DNA array based on allele-specific probes for detection of 118 mutations causing familial hypercholesterolemia. | Tejedor D | Clinical chemistry | 2005 | PMID: 15890894 |
Molecular characterization of familial hypercholesterolemia in Spain: identification of 39 novel and 77 recurrent mutations in LDLR. | Mozas P | Human mutation | 2004 | PMID: 15241806 |
Propagation of fetal human RPE cells: preservation of original culture morphology after serial passage. | Song MK | Journal of cellular physiology | 1990 | PMID: 2318907 |
[Internal medicine--where to?]. | Glick S | Harefuah | 1979 | PMID: 540849 |
[Local hyperbaric oxygen therapy of suppurating wounds of the lower extremities]. | Perepelitsa GF | Ortopediia travmatologiia i protezirovanie | 1979 | PMID: 503436 |
[Determination of risk of ulcer disease with the aid of a table of diagnostic coefficients]. | Zaĭtseva RI | Vrachebnoe delo | 1975 | PMID: 1221619 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/553eb123-6677-44dd-acb4-b7cbdf6514e5 | - | - | - | - |
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Text-mined citations for rs730882110 ...
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.