ACMG Guidelines: Pathogenic (i)
ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.12G>A (p.Trp4Ter)
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.
(7)
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
7
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.12G>A (p.Trp4Ter)
Variation ID: 237860 Accession: VCV000237860.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11089560 (GRCh38) [ NCBI UCSC ] 19: 11200236 (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 Jul 29, 2016 Feb 14, 2024 Dec 6, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.12G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Trp4Ter nonsense NM_001195798.2:c.12G>A NP_001182727.1:p.Trp4Ter nonsense NM_001195799.2:c.12G>A NP_001182728.1:p.Trp4Ter nonsense NM_001195800.2:c.12G>A NP_001182729.1:p.Trp4Ter nonsense NM_001195803.2:c.12G>A NP_001182732.1:p.Trp4Ter nonsense NR_163945.1:n.100C>T non-coding transcript variant NC_000019.10:g.11089560G>A NC_000019.9:g.11200236G>A NG_009060.1:g.5180G>A LRG_274:g.5180G>A LRG_274t1:c.12G>A - Protein change
- W4*
- Other names
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FH Nanjing-1
- Canonical SPDI
- NC_000019.10:11089559: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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The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
- 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 | |
| LDLR-AS1 | - | - | - | GRCh38 | - | 204 |
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 (6) |
criteria provided, multiple submitters, no conflicts
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Jan 22, 2020 | RCV000227275.14 | |
| Pathogenic (1) |
criteria provided, single submitter
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Dec 6, 2023 | RCV000791411.6 |
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
|
LDLR-LOVD, British Heart Foundation
Accession: SCV000294414.2
First in ClinVar: Jul 29, 2016 Last updated: May 19, 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
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Pathogenic
(Mar 30, 2017)
|
criteria provided, single submitter
Method: clinical testing
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Familial Hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille
Accession: SCV000583622.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016
Comment:
ACMG Guidelines: Pathogenic (i)
|
Comment:
ACMG Guidelines: Pathogenic (i)
Number of individuals with the variant: 2
Clinical Features:
Hyperbetalipoproteinemia (present) , Hypercholesterolemia (present)
Indication for testing: Familial Hypercholesterolemia
Sex: mixed
Geographic origin: France
Comment on evidence:
Dutch Lipid Clinic Scoring : Definite FH
Secondary finding: no
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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
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Fundacion Hipercolesterolemia Familiar
Study: SAFEHEART
Accession: SCV000607403.1 First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Observation 1: Observation 2:
Comment on evidence:
Comp Htz (with p.(Leu672*)) patients' fibroblasts, 125I-LDL assays
Result:
<2% LDLR activity
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Pathogenic
(Dec 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000285010.8
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Trp4*) 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.Trp4*) 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 present in population databases (rs756039188, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 7903864, 16314194, 20428891, 21376320, 21868016). ClinVar contains an entry for this variant (Variation ID: 237860). For these reasons, this variant has been classified as Pathogenic. (less)
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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
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Iberoamerican FH Network
Accession: SCV000748035.1
First in ClinVar: May 19, 2018 Last updated: May 19, 2018
Comment:
Variant present in the database from Mexico
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Observation 1: Observation 2:
Comment on evidence:
Assay Description:Comp Htz (with p.(Leu672*)) patients' fibroblasts, 125I-LDL assays
Result:
<2% LDLR activity
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Pathogenic
(Jan 22, 2020)
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criteria provided, single submitter
Method: curation
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Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001422788.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 02, 2022 |
Comment:
The p.Trp4Ter (sometimes called p.Trp-18Ter) variant in LDLR has been reported in 53 individuals (including including 48 Spanish, 3 Chinese, and 2 Mexican individuals) with … (more)
The p.Trp4Ter (sometimes called p.Trp-18Ter) variant in LDLR has been reported in 53 individuals (including including 48 Spanish, 3 Chinese, and 2 Mexican individuals) with Familial Hypercholesterolemia, segregated with disease in 3 affected relatives from 1 family (PMID: 7903864, 20428891, 21868016, 1301956, 16314194), and has been identified in 0.002897% (1/34516) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs756039188). 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 pathogenic in ClinVar (Variation ID: 237860). This nonsense variant leads to a premature termination codon at position 4, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the LDLR gene is an established disease mechanism in Familial Hypercholesterolemia. One pathogenic variant with the same amino acid change as this variant has been reported in association with Familial Hypercholesterolemia in ClinVar, supporting that this variant may be pathogenic (Variation ID: 250973). In summary, this variant meets criteria to be classified as pathogenic for Familial Hypercholesterolemia in an autosomal dominant manner based on the predicted impact of the variant and multiple occurrences in individuals with Familial Hypercholesterolemia. ACMG/AMP Criteria applied: PVS1, PS1, PS4, PP1 (Richards 2015). (less)
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Pathogenic
(Jul 29, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002017124.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Trp4*) 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 present in population databases (rs756039188, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 7903864, 16314194, 20428891, 21376320, 21868016). ClinVar contains an entry for this variant (Variation ID: 237860). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.Trp4Ter (sometimes called p.Trp-18Ter) variant in LDLR has been reported in 53 individuals (including including 48 Spanish, 3 Chinese, and 2 Mexican individuals) with Familial Hypercholesterolemia, segregated with disease in 3 affected relatives from 1 family (PMID: 7903864, 20428891, 21868016, 1301956, 16314194), and has been identified in 0.002897% (1/34516) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs756039188). 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 pathogenic in ClinVar (Variation ID: 237860). This nonsense variant leads to a premature termination codon at position 4, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the LDLR gene is an established disease mechanism in Familial Hypercholesterolemia. One pathogenic variant with the same amino acid change as this variant has been reported in association with Familial Hypercholesterolemia in ClinVar, supporting that this variant may be pathogenic (Variation ID: 250973). In summary, this variant meets criteria to be classified as pathogenic for Familial Hypercholesterolemia in an autosomal dominant manner based on the predicted impact of the variant and multiple occurrences in individuals with Familial Hypercholesterolemia. ACMG/AMP Criteria applied: PVS1, PS1, PS4, PP1 (Richards 2015).
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:
ACMG Guidelines: Pathogenic (i)
Comment:
This sequence change creates a premature translational stop signal (p.Trp4*) 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 present in population databases (rs756039188, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 7903864, 16314194, 20428891, 21376320, 21868016). ClinVar contains an entry for this variant (Variation ID: 237860). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.Trp4Ter (sometimes called p.Trp-18Ter) variant in LDLR has been reported in 53 individuals (including including 48 Spanish, 3 Chinese, and 2 Mexican individuals) with Familial Hypercholesterolemia, segregated with disease in 3 affected relatives from 1 family (PMID: 7903864, 20428891, 21868016, 1301956, 16314194), and has been identified in 0.002897% (1/34516) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs756039188). 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 pathogenic in ClinVar (Variation ID: 237860). This nonsense variant leads to a premature termination codon at position 4, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the LDLR gene is an established disease mechanism in Familial Hypercholesterolemia. One pathogenic variant with the same amino acid change as this variant has been reported in association with Familial Hypercholesterolemia in ClinVar, supporting that this variant may be pathogenic (Variation ID: 250973). In summary, this variant meets criteria to be classified as pathogenic for Familial Hypercholesterolemia in an autosomal dominant manner based on the predicted impact of the variant and multiple occurrences in individuals with Familial Hypercholesterolemia. ACMG/AMP Criteria applied: PVS1, PS1, PS4, PP1 (Richards 2015).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Analysis of LDLR variants from homozygous FH patients carrying multiple mutations in the LDLR gene. | Jiang L | Atherosclerosis | 2017 | PMID: 28645073 |
| Reduced penetrance of autosomal dominant hypercholesterolemia in a high percentage of families: importance of genetic testing in the entire family. | Garcia-Garcia AB | Atherosclerosis | 2011 | PMID: 21868016 |
| Array-based resequencing for mutations causing familial hypercholesterolemia. | Chiou KR | Atherosclerosis | 2011 | PMID: 21376320 |
| Molecular spectrum of autosomal dominant hypercholesterolemia in France. | Marduel M | Human mutation | 2010 | PMID: 20809525 |
| Haplotype analyses, mechanism and evolution of common double mutants in the human LDL receptor gene. | Tejedor MT | Molecular genetics and genomics : MGG | 2010 | PMID: 20428891 |
| Genetic heterogeneity of autosomal dominant hypercholesterolemia in Mexico. | Robles-Osorio L | Archives of medical research | 2006 | PMID: 16314194 |
| Identification of recurrent and novel mutations in the LDL receptor gene in Spanish patients with familial hypercholesterolemia. Mutations in brief no. 135. Online. | Cenarro A | Human mutation | 1998 | PMID: 10206683 |
| Familial hypercholesterolemia in China. Identification of mutations in the LDL-receptor gene that result in a receptor-negative phenotype. | Sun XM | Arteriosclerosis and thrombosis : a journal of vascular biology | 1994 | PMID: 7903864 |
| Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. | Hobbs HH | Human mutation | 1992 | PMID: 1301956 |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/64c91bbe-6858-48a4-9fbe-3d4faa7714df | - | - | - | - |
Text-mined citations for rs756039188 ...
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.