The W810X variant in the LDLR gene has been reported as a novel variant in one patient with FH (Fouchier et al., 2005). This variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other nonsense variants in the LDLR gene have been reported in Human Gene Mutation Database in association with FH (Stenson et al., 2014). Furthermore, the W810X variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server)
ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.2430G>A (p.Trp810Ter)
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
9
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.2430G>A (p.Trp810Ter)
Variation ID: 252335 Accession: VCV000252335.37
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11129553 (GRCh38) [ NCBI UCSC ] 19: 11240229 (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 Apr 27, 2017 Oct 20, 2024 May 24, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.2430G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Trp810Ter nonsense NM_001195798.2:c.2430G>A NP_001182727.1:p.Trp810Ter nonsense NM_001195799.2:c.2307G>A NP_001182728.1:p.Trp769Ter nonsense NM_001195800.2:c.1926G>A NP_001182729.1:p.Trp642Ter nonsense NM_001195803.2:c.1896G>A NP_001182732.1:p.Trp632Ter nonsense NC_000019.10:g.11129553G>A NC_000019.9:g.11240229G>A NG_009060.1:g.45173G>A LRG_274:g.45173G>A LRG_274t1:c.2430G>A LRG_274p1:p.Trp810Ter - Protein change
- W810*, W632*, W642*, W769*
- Other names
- -
- Canonical SPDI
- NC_000019.10:11129552:G:A
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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. |
|||
| 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 (4) |
criteria provided, multiple submitters, no conflicts
|
Aug 13, 2019 | RCV000238147.5 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jun 17, 2021 | RCV000483979.26 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 14, 2023 | RCV001854912.7 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 24, 2024 | RCV004639198.1 |
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 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: SCV000296006.2
First in ClinVar: Jul 29, 2016 Last updated: Sep 30, 2017 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Dec 19, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000568514.4
First in ClinVar: Apr 27, 2017 Last updated: Apr 17, 2019 |
Comment:
The W810X variant in the LDLR gene has been reported as a novel variant in one patient with FH (Fouchier et al., 2005). This variant … (more)
The W810X variant in the LDLR gene has been reported as a novel variant in one patient with FH (Fouchier et al., 2005). This variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other nonsense variants in the LDLR gene have been reported in Human Gene Mutation Database in association with FH (Stenson et al., 2014). Furthermore, the W810X variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server) (less)
|
|
|
Pathogenic
(Aug 13, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001429207.1
First in ClinVar: Aug 16, 2020 Last updated: Aug 16, 2020 |
Number of individuals with the variant: 2
|
|
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Pathogenic
(May 11, 2019)
|
criteria provided, single submitter
Method: research
|
Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
|
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia
Accession: SCV001432639.1
First in ClinVar: Sep 18, 2020 Last updated: Sep 18, 2020 |
Number of individuals with the variant: 1
Clinical Features:
Dutch Lipid Clinic Network Criteria score (present) , low-density lipoprotein cholesterol level (present)
|
|
|
Pathogenic
(Jun 17, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001762193.1
First in ClinVar: Jul 30, 2021 Last updated: Jul 30, 2021 |
Clinical Features:
Varicose disease (present) , Hypercholesterolemia (present) , Abnormality of connective tissue (present) , Bowel diverticulosis (present) , Abnormal esophagus physiology (present) , Recurrent singultus (present)
Sex: female
|
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Pathogenic
(Dec 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002240861.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Trp810*) in the LDLR gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Trp810*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 16250003). ClinVar contains an entry for this variant (Variation ID: 252335). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(May 24, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV005135993.1
First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
Comment:
The p.W810* pathogenic mutation (also known as c.2430G>A), located in coding exon 17 of the LDLR gene, results from a G to A substitution at … (more)
The p.W810* pathogenic mutation (also known as c.2430G>A), located in coding exon 17 of the LDLR gene, results from a G to A substitution at nucleotide position 2430. This changes the amino acid from a tryptophan to a stop codon within coding exon 17. This pathogenic variant has been reported in association with familial hypercholesterolemia (FH) (Fouchier SW et al. Hum Mutat, 2005 Dec;26:550-6; Meshkov A et al. Genes (Basel), 2021 Jan;12:). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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
(Jan 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001246013.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
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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: SCV000606651.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
|
Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Trp810*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 16250003). ClinVar contains an entry for this variant (Variation ID: 252335). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.W810* pathogenic mutation (also known as c.2430G>A), located in coding exon 17 of the LDLR gene, results from a G to A substitution at nucleotide position 2430. This changes the amino acid from a tryptophan to a stop codon within coding exon 17. This pathogenic variant has been reported in association with familial hypercholesterolemia (FH) (Fouchier SW et al. Hum Mutat, 2005 Dec;26:550-6; Meshkov A et al. Genes (Basel), 2021 Jan;12:). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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:
The W810X variant in the LDLR gene has been reported as a novel variant in one patient with FH (Fouchier et al., 2005). This variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other nonsense variants in the LDLR gene have been reported in Human Gene Mutation Database in association with FH (Stenson et al., 2014). Furthermore, the W810X variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server)
Comment:
This sequence change creates a premature translational stop signal (p.Trp810*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 16250003). ClinVar contains an entry for this variant (Variation ID: 252335). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.W810* pathogenic mutation (also known as c.2430G>A), located in coding exon 17 of the LDLR gene, results from a G to A substitution at nucleotide position 2430. This changes the amino acid from a tryptophan to a stop codon within coding exon 17. This pathogenic variant has been reported in association with familial hypercholesterolemia (FH) (Fouchier SW et al. Hum Mutat, 2005 Dec;26:550-6; Meshkov A et al. Genes (Basel), 2021 Jan;12:). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 |
|---|---|---|---|---|
| The LDLR, APOB, and PCSK9 Variants of Index Patients with Familial Hypercholesterolemia in Russia. | Meshkov A | Genes | 2021 | PMID: 33418990 |
| Analysis of LDLR variants from homozygous FH patients carrying multiple mutations in the LDLR gene. | Jiang L | Atherosclerosis | 2017 | PMID: 28645073 |
| Molecular spectrum of autosomal dominant hypercholesterolemia in France. | Marduel M | Human mutation | 2010 | PMID: 20809525 |
| Update of the molecular basis of familial hypercholesterolemia in The Netherlands. | Fouchier SW | Human mutation | 2005 | PMID: 16250003 |
Text-mined citations for rs879255210 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 20, 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.