Variant summary: LDLR c.2431A>T (p.Lys811X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251434 control chromosomes. c.2431A>T has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia and is one of the most common Japanese mutations (eg. Tada_2020, etc). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.2431A>T (p.Lys811Ter)
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.
(6)
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
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000527.5(LDLR):c.2431A>T (p.Lys811Ter)
Variation ID: 252336 Accession: VCV000252336.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11129554 (GRCh38) [ NCBI UCSC ] 19: 11240230 (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 Aug 13, 2017 May 1, 2024 Dec 12, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.2431A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Lys811Ter nonsense NM_001195798.2:c.2431A>T NP_001182727.1:p.Lys811Ter nonsense NM_001195799.2:c.2308A>T NP_001182728.1:p.Lys770Ter nonsense NM_001195800.2:c.1927A>T NP_001182729.1:p.Lys643Ter nonsense NM_001195803.2:c.1897A>T NP_001182732.1:p.Lys633Ter nonsense NC_000019.10:g.11129554A>T NC_000019.9:g.11240230A>T NG_009060.1:g.45174A>T LRG_274:g.45174A>T LRG_274t1:c.2431A>T LRG_274p1:p.Lys811Ter - Protein change
- K811*, K633*, K643*, K770*
- Other names
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FH Tokyo
- Canonical SPDI
- NC_000019.10:11129553: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
Help
The frequency of the allele represented by this VCV record.
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- 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. |
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| 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 (3) |
criteria provided, multiple submitters, no conflicts
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Mar 25, 2016 | RCV000237271.4 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 12, 2023 | RCV000816738.6 | |
| Pathogenic (1) |
criteria provided, single submitter
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Sep 30, 2020 | RCV002450751.2 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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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: SCV000296007.2
First in ClinVar: Jul 29, 2016 Last updated: Sep 30, 2017 |
Number of individuals with the variant: 1
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Pathogenic
(Mar 01, 2016)
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criteria provided, single submitter
Method: research
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Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory of Genetics and Molecular Cardiology, University of São Paulo
Study: HipercolBrasil
Accession: SCV000588666.1 First in ClinVar: Aug 13, 2017 Last updated: Aug 13, 2017 |
Observation 1: Observation 2:
Comment on evidence:
Assay description:Comp Htz (with p.(Glu140Lys); or p.(Leu568Val)) patients' fibroblasts, 125I-LDL assays, just binding
Result:
(p.(Glu140Lys)) 15%; (p.(Leu568Val)) 40% LDL-LDLR binding
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Pathogenic
(Dec 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004240929.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
Variant summary: LDLR c.2431A>T (p.Lys811X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: LDLR c.2431A>T (p.Lys811X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251434 control chromosomes. c.2431A>T has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia and is one of the most common Japanese mutations (eg. Tada_2020, etc). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(May 31, 2023)
|
criteria provided, single submitter
Method: clinical testing
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000957260.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 252336). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the … (more)
ClinVar contains an entry for this variant (Variation ID: 252336). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant is also known as K790X. This premature translational stop signal has been observed in individuals with hypercholesterolemia in a family and in several unrelated affected individuals (PMID: 7583548, 19013141, 21872251). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys811*) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). (less)
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Pathogenic
(Sep 30, 2020)
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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: SCV002737520.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.K811* pathogenic mutation (also known as c.2431A>T), located in coding exon 17 of the LDLR gene, results from an A to T substitution at … (more)
The p.K811* pathogenic mutation (also known as c.2431A>T), located in coding exon 17 of the LDLR gene, results from an A to T substitution at nucleotide position 2431. This changes the amino acid from a lysine to a stop codon within coding exon 17. This alteration (also reported with legacy nomenclature as p.K790*) is one of the most common LDLR mutations found in Japan, and it has been detected in the heterozygous, compound heterozygous, and homozygous state in individuals with familial hypercholesterolemia (Maruyama T et al. Arterioscler. Thromb. Vasc. Biol., 1995 Oct;15:1713-8; Yu W et al. Atherosclerosis, 2002 Dec;165:335-42; Mabuchi H et al. Atherosclerosis, 2011 Feb;214:404-7). It has also been reported to segregate with disease in at least one family (Tada H et al. Atherosclerosis, 2011 Dec;219:663-6). Lymphocytes derived from patients heterozygous with this alteration exhibited approximately 55% of control LDLR activity (Tada H et al. Clin. Chim. Acta, 2009 Feb;400:42-7). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
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Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum
Accession: SCV000606652.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
|
Comment:
Comment:
ClinVar contains an entry for this variant (Variation ID: 252336). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant is also known as K790X. This premature translational stop signal has been observed in individuals with hypercholesterolemia in a family and in several unrelated affected individuals (PMID: 7583548, 19013141, 21872251). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys811*) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073).
Comment:
The p.K811* pathogenic mutation (also known as c.2431A>T), located in coding exon 17 of the LDLR gene, results from an A to T substitution at nucleotide position 2431. This changes the amino acid from a lysine to a stop codon within coding exon 17. This alteration (also reported with legacy nomenclature as p.K790*) is one of the most common LDLR mutations found in Japan, and it has been detected in the heterozygous, compound heterozygous, and homozygous state in individuals with familial hypercholesterolemia (Maruyama T et al. Arterioscler. Thromb. Vasc. Biol., 1995 Oct;15:1713-8; Yu W et al. Atherosclerosis, 2002 Dec;165:335-42; Mabuchi H et al. Atherosclerosis, 2011 Feb;214:404-7). It has also been reported to segregate with disease in at least one family (Tada H et al. Atherosclerosis, 2011 Dec;219:663-6). Lymphocytes derived from patients heterozygous with this alteration exhibited approximately 55% of control LDLR activity (Tada H et al. Clin. Chim. Acta, 2009 Feb;400:42-7). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
Variant summary: LDLR c.2431A>T (p.Lys811X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251434 control chromosomes. c.2431A>T has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia and is one of the most common Japanese mutations (eg. Tada_2020, etc). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
ClinVar contains an entry for this variant (Variation ID: 252336). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant is also known as K790X. This premature translational stop signal has been observed in individuals with hypercholesterolemia in a family and in several unrelated affected individuals (PMID: 7583548, 19013141, 21872251). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys811*) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073).
Comment:
The p.K811* pathogenic mutation (also known as c.2431A>T), located in coding exon 17 of the LDLR gene, results from an A to T substitution at nucleotide position 2431. This changes the amino acid from a lysine to a stop codon within coding exon 17. This alteration (also reported with legacy nomenclature as p.K790*) is one of the most common LDLR mutations found in Japan, and it has been detected in the heterozygous, compound heterozygous, and homozygous state in individuals with familial hypercholesterolemia (Maruyama T et al. Arterioscler. Thromb. Vasc. Biol., 1995 Oct;15:1713-8; Yu W et al. Atherosclerosis, 2002 Dec;165:335-42; Mabuchi H et al. Atherosclerosis, 2011 Feb;214:404-7). It has also been reported to segregate with disease in at least one family (Tada H et al. Atherosclerosis, 2011 Dec;219:663-6). Lymphocytes derived from patients heterozygous with this alteration exhibited approximately 55% of control LDLR activity (Tada H et al. Clin. Chim. Acta, 2009 Feb;400:42-7). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| A catalog of the pathogenic mutations of LDL receptor gene in Japanese familial hypercholesterolemia. | Tada H | Journal of clinical lipidology | 2020 | PMID: 32331935 |
| Analysis of LDLR variants from homozygous FH patients carrying multiple mutations in the LDLR gene. | Jiang L | Atherosclerosis | 2017 | PMID: 28645073 |
| A novel type of familial hypercholesterolemia: double heterozygous mutations in LDL receptor and LDL receptor adaptor protein 1 gene. | Tada H | Atherosclerosis | 2011 | PMID: 21872251 |
| Molecular genetic epidemiology of homozygous familial hypercholesterolemia in the Hokuriku district of Japan. | Mabuchi H | Atherosclerosis | 2011 | PMID: 21146822 |
| Molecular spectrum of autosomal dominant hypercholesterolemia in France. | Marduel M | Human mutation | 2010 | PMID: 20809525 |
| A novel method for determining functional LDL receptor activity in familial hypercholesterolemia: application of the CD3/CD28 assay in lymphocytes. | Tada H | Clinica chimica acta; international journal of clinical chemistry | 2009 | PMID: 19013141 |
| Update of Japanese common LDLR gene mutations and their phenotypes: Mild type mutation L547V might predominate in the Japanese population. | Miyake Y | Atherosclerosis | 2009 | PMID: 18718593 |
| Molecular genetic analysis of familial hypercholesterolemia: spectrum and regional difference of LDL receptor gene mutations in Japanese population. | Yu W | Atherosclerosis | 2002 | PMID: 12417285 |
| Common mutations in the low-density-lipoprotein-receptor gene causing familial hypercholesterolemia in the Japanese population. | Maruyama T | Arteriosclerosis, thrombosis, and vascular biology | 1995 | PMID: 7583548 |
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.