subjects mutated among 2600 FH index cases screened = 9 , family member = 1 with co-segregation
ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.1681C>T (p.Gln561Ter)
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.1681C>T (p.Gln561Ter)
Variation ID: 251965 Accession: VCV000251965.5
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11116188 (GRCh38) [ NCBI UCSC ] 19: 11226864 (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 Apr 20, 2024 Aug 14, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.1681C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Gln561Ter nonsense NM_001195798.2:c.1681C>T NP_001182727.1:p.Gln561Ter nonsense NM_001195799.2:c.1558C>T NP_001182728.1:p.Gln520Ter nonsense NM_001195800.2:c.1177C>T NP_001182729.1:p.Gln393Ter nonsense NM_001195803.2:c.1300C>T NP_001182732.1:p.Gln434Ter nonsense NC_000019.10:g.11116188C>T NC_000019.9:g.11226864C>T NG_009060.1:g.31808C>T LRG_274:g.31808C>T LRG_274t1:c.1681C>T LRG_274p1:p.Gln561Ter - Protein change
- Q561*, Q520*, Q393*, Q434*
- Other names
- -
- Canonical SPDI
- NC_000019.10:11116187:C: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. |
|||
| LDLR | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
4075 | 4351 | |
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
|
Jan 2, 2018 | RCV000238180.6 | |
|
LDLR-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
Mar 21, 2023 | RCV003391008.4 |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 14, 2023 | RCV003581630.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 12, 2019 | RCV004017562.1 |
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: SCV000295571.2
First in ClinVar: Jul 29, 2016 Last updated: Sep 30, 2017 |
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
(Dec 16, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
|
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix
Accession: SCV000503382.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Comment:
subjects mutated among 2600 FH index cases screened = 9 , family member = 1 with co-segregation
Number of individuals with the variant: 9
|
|
|
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: SCV000583860.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016
Comment:
ACMG Guidelines: Pathogenic (i)
|
Number of individuals with the variant: 10
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)
|
criteria provided, single submitter
Method: curation, literature only
|
Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown, not applicable
Allele origin:
germline,
not applicable
|
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge
Accession: SCV000599377.1
First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017 |
Observation 1: Observation 2:
Comment on evidence:
Assay Description:Hmz patients's fibroblasts, 125I-LDL and immunoblotting assays
Result:
<1% LDLR activity; no immunodetectable protein in cells
|
|
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Pathogenic
(Jan 02, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Robarts Research Institute, Western University
Accession: SCV000782921.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
|
|
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Pathogenic
(Mar 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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LDLR-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004110373.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The LDLR c.1681C>T variant is predicted to result in premature protein termination (p.Gln561*). This variant is also described using legacy nomenclature as p.Gln540*, has been … (more)
The LDLR c.1681C>T variant is predicted to result in premature protein termination (p.Gln561*). This variant is also described using legacy nomenclature as p.Gln540*, has been reported in the heterozygous and homozygous states in individuals with hypercholesterolemia (Webb et al. 1996. PubMed ID: 9026534; Amsellem et al. 2002. PubMed ID: 12436241). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in LDLR are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Aug 14, 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: SCV004298369.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 251965). This variant is also known … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 251965). This variant is also known as Gln540*. This premature translational stop signal has been observed in individual(s) with clinical features of LDLR-related conditions (PMID: 8292093, 32041611). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln561*) 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
(Apr 12, 2019)
|
criteria provided, single submitter
Method: clinical testing
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Homozygous familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004847697.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Gln561X variant in LDLR (also described as p.Gln440X in the literature) has been reported in >10 individuals with familial hypercholesterolemia (FH), including one homozygous … (more)
The p.Gln561X variant in LDLR (also described as p.Gln440X in the literature) has been reported in >10 individuals with familial hypercholesterolemia (FH), including one homozygous individual where the variant segregated with disease in at least 4 affected family members (Feher 1993, Webb 1996, Amsellem 2002, Vandrovcova 2013, ClinVar submission accessions: SCV000503382.1, SCV000583860.1). It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 561, which is predicted to lead to a truncated or absent protein. Additionally, in vitro functional studies support an impact on protein function (Webb 1996). Loss of function of the LDLR gene is an established disease mechanism in autosomal dominant FH. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PVS1, PM2, PP1_Supporting, PS3_Supporting, PS4_Moderate. (less)
|
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: research
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum
Accession: SCV000606479.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
|
Comment:
Comment:
The LDLR c.1681C>T variant is predicted to result in premature protein termination (p.Gln561*). This variant is also described using legacy nomenclature as p.Gln540*, has been reported in the heterozygous and homozygous states in individuals with hypercholesterolemia (Webb et al. 1996. PubMed ID: 9026534; Amsellem et al. 2002. PubMed ID: 12436241). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in LDLR are expected to be pathogenic. This variant is interpreted as pathogenic.
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 251965). This variant is also known as Gln540*. This premature translational stop signal has been observed in individual(s) with clinical features of LDLR-related conditions (PMID: 8292093, 32041611). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln561*) 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.Gln561X variant in LDLR (also described as p.Gln440X in the literature) has been reported in >10 individuals with familial hypercholesterolemia (FH), including one homozygous individual where the variant segregated with disease in at least 4 affected family members (Feher 1993, Webb 1996, Amsellem 2002, Vandrovcova 2013, ClinVar submission accessions: SCV000503382.1, SCV000583860.1). It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 561, which is predicted to lead to a truncated or absent protein. Additionally, in vitro functional studies support an impact on protein function (Webb 1996). Loss of function of the LDLR gene is an established disease mechanism in autosomal dominant FH. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PVS1, PM2, PP1_Supporting, PS3_Supporting, PS4_Moderate.
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:
subjects mutated among 2600 FH index cases screened = 9 , family member = 1 with co-segregation
Comment:
The LDLR c.1681C>T variant is predicted to result in premature protein termination (p.Gln561*). This variant is also described using legacy nomenclature as p.Gln540*, has been reported in the heterozygous and homozygous states in individuals with hypercholesterolemia (Webb et al. 1996. PubMed ID: 9026534; Amsellem et al. 2002. PubMed ID: 12436241). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in LDLR are expected to be pathogenic. This variant is interpreted as pathogenic.
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 251965). This variant is also known as Gln540*. This premature translational stop signal has been observed in individual(s) with clinical features of LDLR-related conditions (PMID: 8292093, 32041611). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln561*) 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.Gln561X variant in LDLR (also described as p.Gln440X in the literature) has been reported in >10 individuals with familial hypercholesterolemia (FH), including one homozygous individual where the variant segregated with disease in at least 4 affected family members (Feher 1993, Webb 1996, Amsellem 2002, Vandrovcova 2013, ClinVar submission accessions: SCV000503382.1, SCV000583860.1). It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 561, which is predicted to lead to a truncated or absent protein. Additionally, in vitro functional studies support an impact on protein function (Webb 1996). Loss of function of the LDLR gene is an established disease mechanism in autosomal dominant FH. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PVS1, PM2, PP1_Supporting, PS3_Supporting, PS4_Moderate.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| Analysis of LDLR variants from homozygous FH patients carrying multiple mutations in the LDLR gene. | Jiang L | Atherosclerosis | 2017 | PMID: 28645073 |
| The use of next-generation sequencing in clinical diagnosis of familial hypercholesterolemia. | Vandrovcova J | Genetics in medicine : official journal of the American College of Medical Genetics | 2013 | PMID: 23680767 |
| Molecular spectrum of autosomal dominant hypercholesterolemia in France. | Marduel M | Human mutation | 2010 | PMID: 20809525 |
| Intronic mutations outside of Alu-repeat-rich domains of the LDL receptor gene are a cause of familial hypercholesterolemia. | Amsellem S | Human genetics | 2002 | PMID: 12436241 |
| Characterization of mutations in the low density lipoprotein (LDL)-receptor gene in patients with homozygous familial hypercholesterolemia, and frequency of these mutations in FH patients in the United Kingdom. | Webb JC | Journal of lipid research | 1996 | PMID: 9026534 |
| Cholesterol-lowering drug therapy in a patient with receptor-negative homozygous familial hypercholesterolaemia. | Feher MD | Atherosclerosis | 1993 | PMID: 8292093 |
Text-mined citations for rs879254981 ...
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.