Variant summary: LDLR c.2271delT (p.Leu759SerfsX6) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 251296 control chromosomes (gnomAD). c.2271delT has been reported in the literature in multiple homozygous and heterozygous individuals affected with Familial Hypercholesterolemia (examples: Robles-Osorio_2006, Hernandez-Flores_2018). These data indicate that the variant is very likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories 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.2271del (p.Leu759fs)
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.2271del (p.Leu759fs)
Variation ID: 226388 Accession: VCV000226388.21
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11123304 (GRCh38) [ NCBI UCSC ] 19: 11233980 (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 May 22, 2016 Sep 16, 2024 Mar 24, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.2271del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Leu759fs frameshift NM_000527.4:c.2271delT NM_001195798.2:c.2271del NP_001182727.1:p.Leu759fs frameshift NM_001195799.2:c.2148del NP_001182728.1:p.Leu718fs frameshift NM_001195800.2:c.1767del NP_001182729.1:p.Leu591fs frameshift NM_001195803.2:c.1737del NP_001182732.1:p.Leu581fs frameshift NC_000019.10:g.11123304del NC_000019.9:g.11233980del NG_009060.1:g.38924del LRG_274:g.38924del - Protein change
- L591fs, L718fs, L759fs, L581fs
- Other names
- -
- Canonical SPDI
- NC_000019.10:11123303: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 (4) |
criteria provided, multiple submitters, no conflicts
|
Mar 30, 2017 | RCV000211650.11 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 24, 2024 | RCV000493493.2 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2022 | RCV001193182.13 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 16, 2023 | RCV002444848.3 |
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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|---|---|---|---|---|---|
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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: SCV000295929.2
First in ClinVar: Jul 29, 2016 Last updated: May 19, 2018 |
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: SCV000583939.1
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 : Definite FH
Secondary finding: no
|
|
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Pathogenic
(Mar 01, 2016)
|
criteria provided, single submitter
Method: research
|
Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Iberoamerican FH Network
Accession: SCV000748061.1
First in ClinVar: May 19, 2018 Last updated: May 19, 2018
Comment:
Variant present in the database from Mexico
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|
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Pathogenic
(Jan 31, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001361872.2
First in ClinVar: Jun 22, 2020 Last updated: Feb 12, 2022 |
Comment:
Variant summary: LDLR c.2271delT (p.Leu759SerfsX6) 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.2271delT (p.Leu759SerfsX6) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 251296 control chromosomes (gnomAD). c.2271delT has been reported in the literature in multiple homozygous and heterozygous individuals affected with Familial Hypercholesterolemia (examples: Robles-Osorio_2006, Hernandez-Flores_2018). These data indicate that the variant is very likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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|
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Pathogenic
(Oct 12, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001734545.2
First in ClinVar: Jun 19, 2021 Last updated: Feb 14, 2024 |
Comment:
This variant deletes 1 nucleotide in exon 15 of the LDLR gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more)
This variant deletes 1 nucleotide in exon 15 of the LDLR gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with familial hypercholesterolemia in Mexico (PMID: 16314194, 21722902, 22089669, 29576406). This variant has been identified in 2/251296 chromosomes 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)
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Pathogenic
(Aug 23, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000627032.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Leu759Serfs*6) 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.Leu759Serfs*6) in the LDLR gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with familial hypercholesterolemia (PMID: 16314194, 22089669). ClinVar contains an entry for this variant (Variation ID: 226388). Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). For these reasons, this variant has been classified as Pathogenic. (less)
|
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Pathogenic
(Feb 16, 2023)
|
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: SCV002733276.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.2271delT pathogenic mutation, located in coding exon 15 of the LDLR gene, results from a deletion of one nucleotide at nucleotide position 2271, causing … (more)
The c.2271delT pathogenic mutation, located in coding exon 15 of the LDLR gene, results from a deletion of one nucleotide at nucleotide position 2271, causing a translational frameshift with a predicted alternate stop codon (p.L759Sfs*6). This mutation has been detected in individuals with heterozygous and homozygous familial hypercholesterolemia (FH) with co-segregation reported in multiple Mexican families (Robles-Osorio L et al. Arch. Med. Res., 2006 Jan;37:102-8; Vaca G et al. Atherosclerosis, 2011 Oct;218:391-6; Hernández Flores TJ et al. J Clin Lipidol., 2018 Mar;12:693-701). 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
(Mar 24, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000582114.4
First in ClinVar: Jul 02, 2017 Last updated: Sep 16, 2024 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Identified in individuals with FH, including in the homozygous or compound heterozygous state in individuals with a clinical diagnosis of HoFH (PMID: 16314194, 21722902, 29576406, 34037665); Not observed at significant frequency in large population cohorts (gnomAD); Also described as Fs736ter743; This variant is associated with the following publications: (PMID: 22089669, 38513336, 28391882, 16314194, 21722902, 35460704, 29576406, 34037665) (less)
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Pathogenic
(Mar 26, 2010)
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no assertion criteria provided
Method: clinical testing
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Familial hypercholesterolemia
Affected status: yes
Allele origin:
germline
|
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital
Accession: SCV000268661.1
First in ClinVar: May 22, 2016 Last updated: May 22, 2016 |
Number of individuals with the variant: 1
|
Comment:
Comment:
This variant deletes 1 nucleotide in exon 15 of the LDLR gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with familial hypercholesterolemia in Mexico (PMID: 16314194, 21722902, 22089669, 29576406). This variant has been identified in 2/251296 chromosomes 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:
This sequence change creates a premature translational stop signal (p.Leu759Serfs*6) in the LDLR gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with familial hypercholesterolemia (PMID: 16314194, 22089669). ClinVar contains an entry for this variant (Variation ID: 226388). Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.2271delT pathogenic mutation, located in coding exon 15 of the LDLR gene, results from a deletion of one nucleotide at nucleotide position 2271, causing a translational frameshift with a predicted alternate stop codon (p.L759Sfs*6). This mutation has been detected in individuals with heterozygous and homozygous familial hypercholesterolemia (FH) with co-segregation reported in multiple Mexican families (Robles-Osorio L et al. Arch. Med. Res., 2006 Jan;37:102-8; Vaca G et al. Atherosclerosis, 2011 Oct;218:391-6; Hernández Flores TJ et al. J Clin Lipidol., 2018 Mar;12:693-701). 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.
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Identified in individuals with FH, including in the homozygous or compound heterozygous state in individuals with a clinical diagnosis of HoFH (PMID: 16314194, 21722902, 29576406, 34037665); Not observed at significant frequency in large population cohorts (gnomAD); Also described as Fs736ter743; This variant is associated with the following publications: (PMID: 22089669, 38513336, 28391882, 16314194, 21722902, 35460704, 29576406, 34037665)
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.2271delT (p.Leu759SerfsX6) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 251296 control chromosomes (gnomAD). c.2271delT has been reported in the literature in multiple homozygous and heterozygous individuals affected with Familial Hypercholesterolemia (examples: Robles-Osorio_2006, Hernandez-Flores_2018). These data indicate that the variant is very likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This variant deletes 1 nucleotide in exon 15 of the LDLR gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with familial hypercholesterolemia in Mexico (PMID: 16314194, 21722902, 22089669, 29576406). This variant has been identified in 2/251296 chromosomes 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:
This sequence change creates a premature translational stop signal (p.Leu759Serfs*6) in the LDLR gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with familial hypercholesterolemia (PMID: 16314194, 22089669). ClinVar contains an entry for this variant (Variation ID: 226388). Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.2271delT pathogenic mutation, located in coding exon 15 of the LDLR gene, results from a deletion of one nucleotide at nucleotide position 2271, causing a translational frameshift with a predicted alternate stop codon (p.L759Sfs*6). This mutation has been detected in individuals with heterozygous and homozygous familial hypercholesterolemia (FH) with co-segregation reported in multiple Mexican families (Robles-Osorio L et al. Arch. Med. Res., 2006 Jan;37:102-8; Vaca G et al. Atherosclerosis, 2011 Oct;218:391-6; Hernández Flores TJ et al. J Clin Lipidol., 2018 Mar;12:693-701). 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.
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Identified in individuals with FH, including in the homozygous or compound heterozygous state in individuals with a clinical diagnosis of HoFH (PMID: 16314194, 21722902, 29576406, 34037665); Not observed at significant frequency in large population cohorts (gnomAD); Also described as Fs736ter743; This variant is associated with the following publications: (PMID: 22089669, 38513336, 28391882, 16314194, 21722902, 35460704, 29576406, 34037665)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Screening of LDLR and APOB gene mutations in Mexican patients with homozygous familial hypercholesterolemia. | Hernández Flores TJ | Journal of clinical lipidology | 2018 | PMID: 29576406 |
| Analysis of LDLR variants from homozygous FH patients carrying multiple mutations in the LDLR gene. | Jiang L | Atherosclerosis | 2017 | PMID: 28645073 |
| [Familial homozygous hypercholesterolemia due to the c2271delT mutation in the LDL receptor gene, detected exclusively in Mexicans]. | Martínez L | Gaceta medica de Mexico | 2011 | PMID: 22089669 |
| Mutational analysis of the LDL receptor and APOB genes in Mexican individuals with autosomal dominant hypercholesterolemia. | Vaca G | Atherosclerosis | 2011 | PMID: 21722902 |
| Molecular spectrum of autosomal dominant hypercholesterolemia in France. | Marduel M | Human mutation | 2010 | PMID: 20809525 |
| Genetic heterogeneity of autosomal dominant hypercholesterolemia in Mexico. | Robles-Osorio L | Archives of medical research | 2006 | PMID: 16314194 |
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.