ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.2475C>G (p.Asn825Lys)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000527.5(LDLR):c.2475C>G (p.Asn825Lys)
Variation ID: 161265 Accession: VCV000161265.22
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19p13.2 19: 11129598 (GRCh38) [ NCBI UCSC ] 19: 11240274 (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 Dec 7, 2014 May 1, 2024 Mar 20, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000527.5:c.2475C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Asn825Lys missense NM_000527.4(LDLR):c.2475C>G NM_001195798.2:c.2475C>G NP_001182727.1:p.Asn825Lys missense NM_001195799.2:c.2352C>G NP_001182728.1:p.Asn784Lys missense NM_001195800.2:c.1971C>G NP_001182729.1:p.Asn657Lys missense NM_001195803.2:c.1941C>G NP_001182732.1:p.Asn647Lys missense NC_000019.10:g.11129598C>G NC_000019.9:g.11240274C>G NG_009060.1:g.45218C>G LRG_274:g.45218C>G LRG_274t1:c.2475C>G LRG_274p1:p.Asn825Lys P01130:p.Asn825Lys - Protein change
- N825K, N647K, N657K, N784K
- Other names
- NP_000518.1:p.N825K
- NM_000527.5(LDLR):c.2475C>G
- Canonical SPDI
- NC_000019.10:11129597:C:G
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
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 | ||
---|---|---|---|---|---|---|
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 |
4064 | 4339 |
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. |
---|---|---|---|---|
Likely pathogenic (7) |
reviewed by expert panel
|
Mar 20, 2023 | RCV000237920.23 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jul 19, 2023 | RCV001228564.13 | |
Likely pathogenic (1) |
no assertion criteria provided
|
Jun 1, 2014 | RCV002051658.10 | |
Pathogenic (1) |
criteria provided, single submitter
|
Sep 29, 2023 | RCV002305450.10 | |
Pathogenic (1) |
criteria provided, single submitter
|
Apr 14, 2023 | RCV002444605.10 |
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. |
|
---|---|---|---|---|---|
Likely pathogenic
(Mar 20, 2023)
|
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: SCV004022384.1 First in ClinVar: Aug 05, 2023 Last updated: Aug 05, 2023 |
Comment:
The NM_000527.5 (LDLR):c.2475C>G (p.Asn825Lys) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PS1, PP4, PS4_Supporting) as defined by … (more)
The NM_000527.5 (LDLR):c.2475C>G (p.Asn825Lys) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PS1, PP4, PS4_Supporting) 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: PM2: PopMax MAF = 0.00002 in European (Non-Finnish) in gnomAD (gnomAD v2.1.1). PP3: REVEL = 0.803. PS1: One other missense variant that leads to the same amino acid change at same codon, NM_000527.5 (LDLR):c.2475C>A (p.Asn825Lys), (ClinVarID 252341), is classified as Pathogenic by these guidelines. PP4: Variant meets PM2 and is identified in >1 index cases who fulfil FH diagnostic criteria after alternative causes of high cholesterol were excluded. PS4_Supporting: Variant meets PM2 and is identified in 5 index cases who fulfil FH diagnostic criteria. Four index cases met DLCN criteria for definite or probable FH: 1 case from Department of Medicine and Cardiology, Aarhus Amtssygehus University Hospital, Denmark, PMID 10532689; 1 case from Department of Vascular Medicine, Academic Medical Center at the University of Amsterdam, The Netherlands, PMID 11810272; 1 case from Robarts Research Institute, Canada, PMID 11668627; 1 case submitted to ClinVar from U4M - Lille University & CHRU Lille, France. One proband with LDLC >10mmol/l and xanthoma, reported by Jiang et al, 2016, Department of atherosclerosis, Capital Medical University, China, PMID 27830735. (less)
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Robarts Research Institute, Western University
Accession: SCV000484701.1
First in ClinVar: Dec 17, 2016 Last updated: Dec 17, 2016 |
Number of individuals with the variant: 2
|
|
Pathogenic
(Sep 29, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002599994.3
First in ClinVar: Nov 13, 2022 Last updated: Nov 25, 2023 |
Comment:
Reported in a patient with atrioventricular block in published literature (Resdal Dyssekilde et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); … (more)
Reported in a patient with atrioventricular block in published literature (Resdal Dyssekilde et al., 2022); 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 p.(N804K); This variant is associated with the following publications: (PMID: 25637381, 25487149, 11137106, 11810272, 11668627, 15199436, 23375686, 28323660, 16424354, 17426749, 34407635, 34037665, 19318025, 21310417, 35470684, 10532689, 33740630, 18096825, 27830735, 15576851, 30777337, 37719435, 25378237) (less)
|
|
Likely pathogenic
(Mar 25, 2016)
|
criteria provided, single submitter
Method: literature only
|
Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
LDLR-LOVD, British Heart Foundation
Accession: SCV000296017.2
First in ClinVar: Jul 29, 2016 Last updated: May 03, 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
Observation 5:
Number of individuals with the variant: 1
|
|
Pathogenic
(Mar 30, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Familial Hypercholesterolemia
Affected status: yes
Allele origin:
germline
|
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille
Accession: SCV000583956.1
First in ClinVar: Dec 17, 2016 Last updated: Dec 17, 2016
Comment:
ACMG Guidelines: Pathogenic (ii)
|
Number of individuals with the variant: 1
Clinical Features:
Hyperbetalipoproteinemia (present) , Hypercholesterolemia (present)
Indication for testing: Familial Hypercholesterolemia
Geographic origin: France
Comment on evidence:
Dutch Lipid Clinic Scoring : Definite FH
Secondary finding: no
|
|
Pathogenic
(Jan 22, 2020)
|
criteria provided, single submitter
Method: curation
|
Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001422630.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 02, 2022 |
Comment:
The p.Asn825Lys variant in LDLR has been reported in 75 individuals (including 71 Norweigans, 2 Italian, and 1 Danish, and 1 Dutch individuals) with Familial … (more)
The p.Asn825Lys variant in LDLR has been reported in 75 individuals (including 71 Norweigans, 2 Italian, and 1 Danish, and 1 Dutch individuals) with Familial Hypercholesterolemia, segregated with disease in 71 affected relatives from 19 families (PMID: 15199436, 11810272, 23375686, 11668627, 10532689), and has been identified in 0.001758% (2/113744) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs374045590). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic and pathogenic in ClinVar (Variation ID: 161265). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional variant with the same amino acid change, c.2475C>A (p.Asn825Lys), has been reported pathogenic and likely pathogenic in association with disease in ClinVar and the literature, supporting that this variant is pathogenic (Variation ID: 252341). In summary, this variant meets criteria to be classified as pathogenic for Familial Hypercholesterolemia in an autosomal dominant manner based on multiple reports of individuals with disease and cosegregation with Familial Hypercholesterolemia. ACMG/AMP Criteria applied: PS4, PP1_Strong, PS1, PP3 (Richards 2015). (less)
|
|
Likely pathogenic
(Feb 15, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002022673.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
Pathogenic
(Jul 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001400967.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
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) … (more)
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. ClinVar contains an entry for this variant (Variation ID: 161265). This variant is also known as N804K. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 11668627, 18096825, 27765764, 27830735). This variant is present in population databases (rs374045590, gnomAD 0.0009%). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 825 of the LDLR protein (p.Asn825Lys). Experimental studies have shown that this missense change affects LDLR function (PMID: 25378237). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Apr 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002735625.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.N825K pathogenic mutation (also known as c.2475C>G), located in coding exon 17 of the LDLR gene, results from a C to G substitution at … (more)
The p.N825K pathogenic mutation (also known as c.2475C>G), located in coding exon 17 of the LDLR gene, results from a C to G substitution at nucleotide position 2475. The asparagine at codon 825 is replaced by lysine, an amino acid with similar properties, and is located in the FxNPxY domain. This alteration (also referred to as N804K), and another nucleotide substitution (c.2475C>A) resulting in the same amino acid change have been detected in many individuals from familial hypercholesterolemia cohorts (Jensen HK et al. Atherosclerosis, 1999 Oct;146:337-44; Leren TP et al. Semin Vasc Med, 2004 Feb;4:75-85; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Chaves FJ et al. J. Clin. Endocrinol. Metab., 2001 Oct;86:4926-32; Brusgaard K et al. Clin. Genet., 2006 Mar;69:277-83; Mozas P et al. Hum. Mutat., 2004 Aug;24:187). This alteration was also reported to segregate with hypercholesterolemia in several individuals in one family (Berge KE et al. Arterioscler. Thromb. Vasc. Biol., 2006 May;26:1094-100). In addition, experimental studies have indicated this alteration results in impaired LDL internalization and uptake (Etxebarria A et al. Hum. Mutat., 2015 Jan;36:129-41; Rodríguez-Jiménez C et al. Atherosclerosis, 2019 Jan). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
|
|
Likely pathogenic
(Jun 01, 2014)
|
no assertion criteria provided
Method: research
|
Hypercholesterolaemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190283.1 First in ClinVar: Dec 07, 2014 Last updated: Dec 07, 2014
Comment:
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
|
|
|
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: SCV000606657.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
|
|
click to load more click to collapse |
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 |
---|---|---|---|---|
A new variant (c.1A>G) in LDLRAP1 causing autosomal recessive hypercholesterolemia: Characterization of the defect and response to PCSK9 inhibition. | Rodríguez-Jiménez C | Atherosclerosis | 2019 | PMID: 30777337 |
The use of targeted exome sequencing in genetic diagnosis of young patients with severe hypercholesterolemia. | Jiang L | Scientific reports | 2016 | PMID: 27830735 |
Homozygous Familial Hypercholesterolemia in Spain: Prevalence and Phenotype-Genotype Relationship. | Sánchez-Hernández RM | Circulation. Cardiovascular genetics | 2016 | PMID: 27784735 |
Polygenic Versus Monogenic Causes of Hypercholesterolemia Ascertained Clinically. | Wang J | Arteriosclerosis, thrombosis, and vascular biology | 2016 | PMID: 27765764 |
Clinical and molecular characteristics of homozygous familial hypercholesterolemia patients: Insights from SAFEHEART registry. | Alonso R | Journal of clinical lipidology | 2016 | PMID: 27578128 |
Characterization of the unique Chinese W483X mutation in the low-density lipoprotein-receptor gene in young patients with homozygous familial hypercholesterolemia. | Jiang L | Journal of clinical lipidology | 2016 | PMID: 27206941 |
Actionable exomic incidental findings in 6503 participants: challenges of variant classification. | Amendola LM | Genome research | 2015 | PMID: 25637381 |
Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. | Do R | Nature | 2015 | PMID: 25487149 |
Clinically used selective oestrogen receptor modulators increase LDL receptor activity in primary human lymphocytes. | Cerrato F | British journal of pharmacology | 2015 | PMID: 25395200 |
Functional characterization and classification of frequent low-density lipoprotein receptor variants. | Etxebarria A | Human mutation | 2015 | PMID: 25378237 |
Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. | Bertolini S | Atherosclerosis | 2013 | PMID: 23375686 |
Femoral atherosclerosis in heterozygous familial hypercholesterolemia: influence of the genetic defect. | Junyent M | Arteriosclerosis, thrombosis, and vascular biology | 2008 | PMID: 18096825 |
Molecular genetic analysis of 1053 Danish individuals with clinical signs of familial hypercholesterolemia. | Brusgaard K | Clinical genetics | 2006 | PMID: 16542394 |
Missense mutations in the PCSK9 gene are associated with hypocholesterolemia and possibly increased response to statin therapy. | Berge KE | Arteriosclerosis, thrombosis, and vascular biology | 2006 | PMID: 16424354 |
Genetic screening of patients with familial hypercholesterolaemia (FH): a New Zealand perspective. | Laurie AD | Atherosclerosis. Supplements | 2004 | PMID: 15556094 |
Molecular characterization of familial hypercholesterolemia in Spain: identification of 39 novel and 77 recurrent mutations in LDLR. | Mozas P | Human mutation | 2004 | PMID: 15241806 |
Application of molecular genetics for diagnosing familial hypercholesterolemia in Norway: results from a family-based screening program. | Leren TP | Seminars in vascular medicine | 2004 | PMID: 15199436 |
Influence of LDL receptor gene mutations and the R3500Q mutation of the apoB gene on lipoprotein phenotype of familial hypercholesterolemic patients from a South European population. | Real JT | European journal of human genetics : EJHG | 2003 | PMID: 14508510 |
The molecular genetic basis and diagnosis of familial hypercholesterolemia in Denmark. | Jensen HK | Danish medical bulletin | 2002 | PMID: 12553167 |
The molecular basis of familial hypercholesterolemia in The Netherlands. | Fouchier SW | Human genetics | 2001 | PMID: 11810272 |
Molecular genetics of familial hypercholesterolemia in Spain: Ten novel LDLR mutations and population analysis. | García-García AB | Human mutation | 2001 | PMID: 11668640 |
Low density lipoprotein receptor (LDLR) gene mutations in Canadian subjects with familial hypercholesterolemia, but not of French descent. | Wang J | Human mutation | 2001 | PMID: 11668627 |
Genetic diagnosis of familial hypercholesterolemia in a South European outbreed population: influence of low-density lipoprotein (LDL) receptor gene mutations on treatment response to simvastatin in total, LDL, and high-density lipoprotein cholesterol. | Chaves FJ | The Journal of clinical endocrinology and metabolism | 2001 | PMID: 11600564 |
Spectrum of LDL receptor gene mutations in Denmark: implications for molecular diagnostic strategy in heterozygous familial hypercholesterolemia. | Jensen HK | Atherosclerosis | 1999 | PMID: 10532689 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/a366bd5f-25ad-4977-b948-cb45aa320c0c | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/b7022b54-3b8e-470d-8aef-6b0b2b48791e | - | - | - | - |
click to load more click to collapse |
Text-mined citations for rs374045590 ...
HelpRecord last updated Sep 17, 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.