This sequence change creates a premature translational stop signal (p.Trp620*) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 252089). This premature translational stop signal has been observed in individuals with familial hypercholesterolemia (PMID: 20809525, 25846081). This variant is not present in population databases (gnomAD no frequency).
ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.1860G>A (p.Trp620Ter)
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
-
NM_000527.5(LDLR):c.1860G>A (p.Trp620Ter)
Variation ID: 252089 Accession: VCV000252089.19
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19p13.2 19: 11120106 (GRCh38) [ NCBI UCSC ] 19: 11230782 (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 Jul 29, 2016 May 1, 2024 Oct 23, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.1860G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Trp620Ter nonsense NM_001195798.2:c.1860G>A NP_001182727.1:p.Trp620Ter nonsense NM_001195799.2:c.1737G>A NP_001182728.1:p.Trp579Ter nonsense NM_001195800.2:c.1356G>A NP_001182729.1:p.Trp452Ter nonsense NM_001195803.2:c.1479G>A NP_001182732.1:p.Trp493Ter nonsense NC_000019.10:g.11120106G>A NC_000019.9:g.11230782G>A NG_009060.1:g.35726G>A LRG_274:g.35726G>A LRG_274t1:c.1860G>A LRG_274p1:p.Trp620Ter - Protein change
- W620*, W493*, W452*, W579*
- Other names
-
p.Trp620*
- Canonical SPDI
- NC_000019.10:11120105:G:A
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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.
- -
- 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 (5) |
criteria provided, multiple submitters, no conflicts
|
Oct 23, 2023 | RCV000237143.7 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Sep 1, 2023 | RCV000775248.12 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 24, 2022 | RCV002411099.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 26, 2022 | RCV003480570.1 |
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. |
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|---|---|---|---|---|---|
|
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: SCV000295721.2
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
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: SCV000583899.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016
Comment:
ACMG Guidelines: Pathogenic (i)
|
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 : Probable FH
Secondary finding: no
|
|
|
Pathogenic
(Dec 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000544648.8
First in ClinVar: Jul 29, 2016 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Trp620*) 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.Trp620*) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 252089). This premature translational stop signal has been observed in individuals with familial hypercholesterolemia (PMID: 20809525, 25846081). This variant is not present in population databases (gnomAD no frequency). (less)
|
|
|
Pathogenic
(May 17, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
germline
|
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV000839977.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Comment:
The c.1860G>A (p.Trp620*) variant in the LDLR gene has been reported in one patient with autosomal dominant hypercholesterolemia [PMID 20809525]. This variant also segregated with … (more)
The c.1860G>A (p.Trp620*) variant in the LDLR gene has been reported in one patient with autosomal dominant hypercholesterolemia [PMID 20809525]. This variant also segregated with the phenotype within the reported proband’s family. The c.1860G>A change creates a premature stop codon at amino acid position 620 of the LDLR protein and is thus predicted to result in a loss of function of the protein. The c.1860G>A change has not been reported in the ExAC database. Another nucleotide change (c.1859G>A) similarly resulting a non sense variant at the same amino acid position 620 (p.Trp620*) has also been reported in patients with hypercholesterolemia [PMID 11737238]. This c.1860G>A (p.Trp620*) variant is thus classified as pathogenic. (less)
|
|
|
Pathogenic
(Sep 20, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002813234.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Sep 26, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004227681.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP1, PM2_supporting, PVS1
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Sep 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000909506.2
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This variant changes 1 nucleotide in exon 13 in the LDLR type B repeat 6 of the LDLR gene, creating a premature translation stop signal. … (more)
This variant changes 1 nucleotide in exon 13 in the LDLR type B repeat 6 of the LDLR gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least two individuals affected with familial hypercholesterolemia (PMID: 20809525, 25846081, 28235710) and in one individual suspected to be affected with familial hypercholesterolemia (PMID: 34037665). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
|
|
|
Pathogenic
(Oct 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
(Semidominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004818459.1
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)
|
Comment:
The c.1860G>A (p.Trp620*) variant in the LDLR gene has been reported in one patient with autosomal dominant hypercholesterolemia [PMID 20809525]. This variant also segregated with … (more)
The c.1860G>A (p.Trp620*) variant in the LDLR gene has been reported in one patient with autosomal dominant hypercholesterolemia [PMID 20809525]. This variant also segregated with the phenotype within the reported proband's family. The c.1860G>A change creates a premature stop codon at amino acid position 620 of the LDLR protein and is thus predicted to result in a loss of function of the protein. The c.1860G>A change has not been reported in the ExAC database. Another nucleotide change (c.1859G>A) similarly resulting a non sense variant at the same amino acid position 620 (p.Trp620*) has also been reported in patients with hypercholesterolemia [PMID 11737238]. This c.1860G>A (p.Trp620*) variant is thus classified as pathogenic. (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Jan 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002724100.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.W620* pathogenic mutation (also known as c.1860G>A), located in coding exon 13 of the LDLR gene, results from a G to A substitution at … (more)
The p.W620* pathogenic mutation (also known as c.1860G>A), located in coding exon 13 of the LDLR gene, results from a G to A substitution at nucleotide position 1860. This changes the amino acid from a tryptophan to a stop codon within coding exon 13. This variant has been reported in individuals with familial hypercholesterolemia (FH), segregating with disease in two families (Marduel M et al. Hum Mutat, 2010 Nov;31:E1811-24; Fan LL et al. Appl Biochem Biotechnol, 2015 May;176:101-9; Xiang R et al. Atherosclerosis, 2017 03;258:84-88; Sturm AC et al. JAMA Cardiol, 2021 08;6:902-909). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, 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)
|
Comment:
Comment:
The c.1860G>A (p.Trp620*) variant in the LDLR gene has been reported in one patient with autosomal dominant hypercholesterolemia [PMID 20809525]. This variant also segregated with the phenotype within the reported proband’s family. The c.1860G>A change creates a premature stop codon at amino acid position 620 of the LDLR protein and is thus predicted to result in a loss of function of the protein. The c.1860G>A change has not been reported in the ExAC database. Another nucleotide change (c.1859G>A) similarly resulting a non sense variant at the same amino acid position 620 (p.Trp620*) has also been reported in patients with hypercholesterolemia [PMID 11737238]. This c.1860G>A (p.Trp620*) variant is thus classified as pathogenic.
Comment:
PP1, PM2_supporting, PVS1
Comment:
This variant changes 1 nucleotide in exon 13 in the LDLR type B repeat 6 of the LDLR gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least two individuals affected with familial hypercholesterolemia (PMID: 20809525, 25846081, 28235710) and in one individual suspected to be affected with familial hypercholesterolemia (PMID: 34037665). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
The c.1860G>A (p.Trp620*) variant in the LDLR gene has been reported in one patient with autosomal dominant hypercholesterolemia [PMID 20809525]. This variant also segregated with the phenotype within the reported proband's family. The c.1860G>A change creates a premature stop codon at amino acid position 620 of the LDLR protein and is thus predicted to result in a loss of function of the protein. The c.1860G>A change has not been reported in the ExAC database. Another nucleotide change (c.1859G>A) similarly resulting a non sense variant at the same amino acid position 620 (p.Trp620*) has also been reported in patients with hypercholesterolemia [PMID 11737238]. This c.1860G>A (p.Trp620*) variant is thus classified as pathogenic.
Comment:
The p.W620* pathogenic mutation (also known as c.1860G>A), located in coding exon 13 of the LDLR gene, results from a G to A substitution at nucleotide position 1860. This changes the amino acid from a tryptophan to a stop codon within coding exon 13. This variant has been reported in individuals with familial hypercholesterolemia (FH), segregating with disease in two families (Marduel M et al. Hum Mutat, 2010 Nov;31:E1811-24; Fan LL et al. Appl Biochem Biotechnol, 2015 May;176:101-9; Xiang R et al. Atherosclerosis, 2017 03;258:84-88; Sturm AC et al. JAMA Cardiol, 2021 08;6:902-909). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, 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:
This sequence change creates a premature translational stop signal (p.Trp620*) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 252089). This premature translational stop signal has been observed in individuals with familial hypercholesterolemia (PMID: 20809525, 25846081). This variant is not present in population databases (gnomAD no frequency).
Comment:
The c.1860G>A (p.Trp620*) variant in the LDLR gene has been reported in one patient with autosomal dominant hypercholesterolemia [PMID 20809525]. This variant also segregated with the phenotype within the reported proband’s family. The c.1860G>A change creates a premature stop codon at amino acid position 620 of the LDLR protein and is thus predicted to result in a loss of function of the protein. The c.1860G>A change has not been reported in the ExAC database. Another nucleotide change (c.1859G>A) similarly resulting a non sense variant at the same amino acid position 620 (p.Trp620*) has also been reported in patients with hypercholesterolemia [PMID 11737238]. This c.1860G>A (p.Trp620*) variant is thus classified as pathogenic.
Comment:
PP1, PM2_supporting, PVS1
Comment:
This variant changes 1 nucleotide in exon 13 in the LDLR type B repeat 6 of the LDLR gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least two individuals affected with familial hypercholesterolemia (PMID: 20809525, 25846081, 28235710) and in one individual suspected to be affected with familial hypercholesterolemia (PMID: 34037665). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
The c.1860G>A (p.Trp620*) variant in the LDLR gene has been reported in one patient with autosomal dominant hypercholesterolemia [PMID 20809525]. This variant also segregated with the phenotype within the reported proband's family. The c.1860G>A change creates a premature stop codon at amino acid position 620 of the LDLR protein and is thus predicted to result in a loss of function of the protein. The c.1860G>A change has not been reported in the ExAC database. Another nucleotide change (c.1859G>A) similarly resulting a non sense variant at the same amino acid position 620 (p.Trp620*) has also been reported in patients with hypercholesterolemia [PMID 11737238]. This c.1860G>A (p.Trp620*) variant is thus classified as pathogenic.
Comment:
The p.W620* pathogenic mutation (also known as c.1860G>A), located in coding exon 13 of the LDLR gene, results from a G to A substitution at nucleotide position 1860. This changes the amino acid from a tryptophan to a stop codon within coding exon 13. This variant has been reported in individuals with familial hypercholesterolemia (FH), segregating with disease in two families (Marduel M et al. Hum Mutat, 2010 Nov;31:E1811-24; Fan LL et al. Appl Biochem Biotechnol, 2015 May;176:101-9; Xiang R et al. Atherosclerosis, 2017 03;258:84-88; Sturm AC et al. JAMA Cardiol, 2021 08;6:902-909). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, 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 |
|---|---|---|---|---|
| Limited-Variant Screening vs Comprehensive Genetic Testing for Familial Hypercholesterolemia Diagnosis. | Sturm AC | JAMA cardiology | 2021 | PMID: 34037665 |
| Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network. | eMERGE Consortium. Electronic address: agibbs@bcm.edu | American journal of human genetics | 2019 | PMID: 31447099 |
| Analysis of LDLR variants from homozygous FH patients carrying multiple mutations in the LDLR gene. | Jiang L | Atherosclerosis | 2017 | PMID: 28645073 |
| The genetic spectrum of familial hypercholesterolemia in the central south region of China. | Xiang R | Atherosclerosis | 2017 | PMID: 28235710 |
| Novel mutations of low-density lipoprotein receptor gene in China patients with familial hypercholesterolemia. | Fan LL | Applied biochemistry and biotechnology | 2015 | PMID: 25846081 |
| Molecular spectrum of autosomal dominant hypercholesterolemia in France. | Marduel M | Human mutation | 2010 | PMID: 20809525 |
Text-mined citations for rs875989933 ...
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 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.