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; Published functional studies demonstrate a damaging effect through defective uptake, internalization, and degradation (Davis et al., 1986; Ranheim et al., 2006; Thormaehlen et al., 2015); Also denoted as Y807C and FH J.D-Bari due to the use of alternate nomenclature; This variant is associated with the following publications: (PMID: 23375686, 28126585, 23733886, 189940, 8882879, 19446849, 200368, 31387896, 20145306, 25461735, 3955657, 23105264, 32041611, 33740630, 32719484, 33508743, Thajer2022, 25647241, 16740646)
ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.2483A>G (p.Tyr828Cys)
Germline
Classification
Help
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.
(9)
Help
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.
Pathogenic/Likely pathogenic
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000527.5(LDLR):c.2483A>G (p.Tyr828Cys)
Variation ID: 3704 Accession: VCV000003704.10
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19p13.2 19: 11129606 (GRCh38) [ NCBI UCSC ] 19: 11240282 (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 Apr 4, 2013 May 1, 2024 Jan 5, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.2483A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Tyr828Cys missense NM_001195798.2:c.2483A>G NP_001182727.1:p.Tyr828Cys missense NM_001195799.2:c.2360A>G NP_001182728.1:p.Tyr787Cys missense NM_001195800.2:c.1979A>G NP_001182729.1:p.Tyr660Cys missense NM_001195803.2:c.1949A>G NP_001182732.1:p.Tyr650Cys missense NC_000019.10:g.11129606A>G NC_000019.9:g.11240282A>G NG_009060.1:g.45226A>G LRG_274:g.45226A>G LRG_274t1:c.2483A>G LRG_274p1:p.Tyr828Cys P01130:p.Tyr828Cys - Protein change
- Y828C, Y660C, Y787C, Y650C
- Other names
-
Y807C
FH Bari
FH Syria
FHJ.D-Bari
- Canonical SPDI
- NC_000019.10:11129605:A:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
unknown functional consequenceunclear [submitted by Dept. of Genetics and Pharmacogenomics, Merck Research Labs]
-
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.
- -
- 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 |
4076 | 4352 | |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jul 29, 2022 | RCV000003893.13 | |
| Pathogenic (2) |
criteria provided, single submitter
|
May 6, 2022 | RCV000162025.5 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 5, 2024 | RCV002426485.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 23, 2022 | RCV002512729.3 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Mar 01, 2016)
|
criteria provided, single submitter
Method: research
|
Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory of Genetics and Molecular Cardiology, University of São Paulo
Study: HipercolBrasil
Accession: SCV000588670.1 First in ClinVar: Aug 13, 2017 Last updated: Aug 13, 2017 |
Observation 1: Observation 2:
Comment on evidence:
Assay description:Comp htz (with c.1891_2311+1065delinsCTCAGCACTTTGGG) patients' fibroblasts, 125I-LDL assays / Heterologous cells (CHO), FACS assays / 125I-LDL assays
Result:
normal LDL-LDLR binding, 2-5% LDL-LDLR uptake and degradation / 50-60% LDL-LDLR uptake; normal LDL-LDLR binding and cell surface LDLR / normal LDL-LDLR binding, 25% LDL-LDLR uptake
|
|
|
Pathogenic
(May 06, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002520116.2
First in ClinVar: May 28, 2022 Last updated: Mar 04, 2023 |
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; Published functional studies demonstrate a damaging effect through defective uptake, internalization, and degradation (Davis et al., 1986; Ranheim et al., 2006; Thormaehlen et al., 2015); Also denoted as Y807C and FH J.D-Bari due to the use of alternate nomenclature; This variant is associated with the following publications: (PMID: 23375686, 28126585, 23733886, 189940, 8882879, 19446849, 200368, 31387896, 20145306, 25461735, 3955657, 23105264, 32041611, 33740630, 32719484, 33508743, Thajer2022, 25647241, 16740646) (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: SCV000296023.2
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
|
|
|
Pathogenic
(Jul 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003825411.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Dec 23, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003443111.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LDLR function (PMID: 3955657, 16740646). Advanced … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LDLR function (PMID: 3955657, 16740646). 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: 3704). This variant is also known as p.Tyr807Cys, or JD Bari. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 23375686, 25461735, 28126585, 31387896). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 828 of the LDLR protein (p.Tyr828Cys). (less)
|
|
|
Pathogenic
(Jan 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002740428.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.Y828C pathogenic mutation (also known as c.2483A>G), located in coding exon 17 of the LDLR gene, results from an A to G substitution at … (more)
The p.Y828C pathogenic mutation (also known as c.2483A>G), located in coding exon 17 of the LDLR gene, results from an A to G substitution at nucleotide position 2483. The tyrosine at codon 828 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been described in several patients with familial hypercholesterolemia (FH) (Brown MS et al. Cell, 1976 Dec;9:663-74; Goldstein JL et al. Cell, 1977 Nov;12:629-41; Reshef A et al. Hum Genet. 1996;98:581-6; Chmara M et al. J Appl Genet. 2010;51:95-106; Bertolini S et al. Atherosclerosis. 2013;227:342-8). In functional in vitro analyses, this variant has demonstrated decreased ability to bind and internalize low-density lipoprotein (LDL), thus inhibiting endocytosis (Davis CG et al. Cell. 1986;45:15-24). Internal structural analysis suggests that this variant, which impacts the NPXY motif required for receptor internalization, will disrupt protein function (Chen WJ et al. J Biol Chem. 1990;265(6):3116-23; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (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: SCV000606662.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
|
|
|
Pathogenic
(Apr 11, 1986)
|
no assertion criteria provided
Method: literature only
|
FH BARI
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000024058.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In an Italian patient with FH (143890), Davis et al. (1986) found a TAT-to-TGT mutation in this internalization-defective allele.
|
|
|
not provided
(-)
|
no classification provided
(in vitro)
Method: in vitro
|
not provided
Affected status: not applicable
Allele origin:
not applicable
|
Dept. of Genetics and Pharmacogenomics, Merck Research Labs
Accession: SCV000189628.1
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
|
|
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LDLR function (PMID: 3955657, 16740646). 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: 3704). This variant is also known as p.Tyr807Cys, or JD Bari. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 23375686, 25461735, 28126585, 31387896). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 828 of the LDLR protein (p.Tyr828Cys).
Comment:
The p.Y828C pathogenic mutation (also known as c.2483A>G), located in coding exon 17 of the LDLR gene, results from an A to G substitution at nucleotide position 2483. The tyrosine at codon 828 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been described in several patients with familial hypercholesterolemia (FH) (Brown MS et al. Cell, 1976 Dec;9:663-74; Goldstein JL et al. Cell, 1977 Nov;12:629-41; Reshef A et al. Hum Genet. 1996;98:581-6; Chmara M et al. J Appl Genet. 2010;51:95-106; Bertolini S et al. Atherosclerosis. 2013;227:342-8). In functional in vitro analyses, this variant has demonstrated decreased ability to bind and internalize low-density lipoprotein (LDL), thus inhibiting endocytosis (Davis CG et al. Cell. 1986;45:15-24). Internal structural analysis suggests that this variant, which impacts the NPXY motif required for receptor internalization, will disrupt protein function (Chen WJ et al. J Biol Chem. 1990;265(6):3116-23; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
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. |
|---|---|---|---|---|
|
unknown functional consequence
|
|
|
Dept. of Genetics and Pharmacogenomics, Merck Research Labs
Accession: SCV000189628.1
|
Comment:
unclear
|
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; Published functional studies demonstrate a damaging effect through defective uptake, internalization, and degradation (Davis et al., 1986; Ranheim et al., 2006; Thormaehlen et al., 2015); Also denoted as Y807C and FH J.D-Bari due to the use of alternate nomenclature; This variant is associated with the following publications: (PMID: 23375686, 28126585, 23733886, 189940, 8882879, 19446849, 200368, 31387896, 20145306, 25461735, 3955657, 23105264, 32041611, 33740630, 32719484, 33508743, Thajer2022, 25647241, 16740646)
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LDLR function (PMID: 3955657, 16740646). 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: 3704). This variant is also known as p.Tyr807Cys, or JD Bari. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 23375686, 25461735, 28126585, 31387896). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 828 of the LDLR protein (p.Tyr828Cys).
Comment:
The p.Y828C pathogenic mutation (also known as c.2483A>G), located in coding exon 17 of the LDLR gene, results from an A to G substitution at nucleotide position 2483. The tyrosine at codon 828 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been described in several patients with familial hypercholesterolemia (FH) (Brown MS et al. Cell, 1976 Dec;9:663-74; Goldstein JL et al. Cell, 1977 Nov;12:629-41; Reshef A et al. Hum Genet. 1996;98:581-6; Chmara M et al. J Appl Genet. 2010;51:95-106; Bertolini S et al. Atherosclerosis. 2013;227:342-8). In functional in vitro analyses, this variant has demonstrated decreased ability to bind and internalize low-density lipoprotein (LDL), thus inhibiting endocytosis (Davis CG et al. Cell. 1986;45:15-24). Internal structural analysis suggests that this variant, which impacts the NPXY motif required for receptor internalization, will disrupt protein function (Chen WJ et al. J Biol Chem. 1990;265(6):3116-23; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Population genetic screening efficiently identifies carriers of autosomal dominant diseases. | Grzymski JJ | Nature medicine | 2020 | PMID: 32719484 |
| Six years' experience with LipidSeq: clinical and research learnings from a hybrid, targeted sequencing panel for dyslipidemias. | Dron JS | BMC medical genomics | 2020 | PMID: 32041611 |
| In search of a genetic explanation for LDLc variability in an FH family: common SNPs and a rare mutation in MTTP explain only part of LDL variability in an FH family. | Winther M | Journal of lipid research | 2019 | PMID: 31387896 |
| Homozygous familial hypercholesterolemia: Summarized case reports. | Widhalm K | Atherosclerosis | 2017 | PMID: 28126585 |
| Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France. | Wintjens R | Journal of lipid research | 2016 | PMID: 26802169 |
| 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 |
| Familial hypercholesterolemia in Brazil: cascade screening program, clinical and genetic aspects. | Jannes CE | Atherosclerosis | 2015 | PMID: 25461735 |
| The LXR-IDOL axis defines a clathrin-, caveolae-, and dynamin-independent endocytic route for LDLR internalization and lysosomal degradation. | Sorrentino V | Journal of lipid research | 2013 | PMID: 23733886 |
| Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. | Bertolini S | Atherosclerosis | 2013 | PMID: 23375686 |
| Genetic analysis of familial hypercholesterolaemia in Western Australia. | Hooper AJ | Atherosclerosis | 2012 | PMID: 22883975 |
| Molecular spectrum of autosomal dominant hypercholesterolemia in France. | Marduel M | Human mutation | 2010 | PMID: 20809525 |
| Molecular characterization of Polish patients with familial hypercholesterolemia: novel and recurrent LDLR mutations. | Chmara M | Journal of applied genetics | 2010 | PMID: 20145306 |
| Model system for phenotypic characterization of sequence variations in the LDL receptor gene. | Ranheim T | Clinical chemistry | 2006 | PMID: 16740646 |
| A cholesterol-lowering gene maps to chromosome 13q. | Knoblauch H | American journal of human genetics | 2000 | PMID: 10631147 |
| Molecular genetics of familial hypercholesterolemia in Israel. | Reshef A | Human genetics | 1996 | PMID: 8882879 |
| The J.D. mutation in familial hypercholesterolemia: amino acid substitution in cytoplasmic domain impedes internalization of LDL receptors. | Davis CG | Cell | 1986 | PMID: 3955657 |
| Genetics of the LDL receptor: evidence that the mutations affecting binding and internalization are allelic. | Goldstein JL | Cell | 1977 | PMID: 200368 |
| Analysis of a mutant strain of human fibroblasts with a defect in the internalization of receptor-bound low density lipoprotein. | Brown MS | Cell | 1976 | PMID: 189940 |
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Text-mined citations for this variant ...
HelpRecord 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.