subject mutated among 2600 FH index cases screened = 1 , family member = 1
ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.941-2A>G
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.
(6)
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/Likely pathogenic
6
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.941-2A>G
Variation ID: 251554 Accession: VCV000251554.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11110650 (GRCh38) [ NCBI UCSC ] 19: 11221326 (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 Dec 10, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.941-2A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NM_001195798.2:c.941-2A>G splice acceptor NM_001195799.2:c.818-2A>G splice acceptor NM_001195800.2:c.437-2A>G splice acceptor NM_001195803.2:c.560-2A>G splice acceptor NC_000019.10:g.11110650A>G NC_000019.9:g.11221326A>G NG_009060.1:g.26270A>G LRG_274:g.26270A>G LRG_274t1:c.941-2A>G - Protein change
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- Other names
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- Canonical SPDI
- NC_000019.10:11110649:A:G
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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 |
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. |
|---|---|---|---|---|
| Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Dec 10, 2023 | RCV000237558.6 | |
| Pathogenic (1) |
criteria provided, single submitter
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Aug 8, 2023 | RCV001034626.8 | |
| Likely pathogenic (1) |
criteria provided, single submitter
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Apr 18, 2023 | RCV003477851.1 |
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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|---|---|---|---|---|---|
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Likely pathogenic
(Mar 25, 2016)
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criteria provided, single submitter
Method: literature only
|
Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
LDLR-LOVD, British Heart Foundation
Accession: SCV000295091.2
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
|
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Likely pathogenic
(Dec 16, 2016)
|
criteria provided, single submitter
Method: clinical testing
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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: SCV000503266.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Comment:
subject mutated among 2600 FH index cases screened = 1 , family member = 1
Number of individuals with the variant: 1
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Pathogenic
(Aug 08, 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: SCV000544681.7
First in ClinVar: Jul 29, 2016 Last updated: Feb 28, 2024 |
Comment:
Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, … (more)
Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 251554). This variant is also known as IVS6-2A>G. Disruption of this splice site has been observed in individuals with familial hypercholesterolemia (PMID: 12436241, 25962062). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 6 of the LDLR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). (less)
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Likely pathogenic
(Apr 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004220005.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
This variant disrupts a canonical splice-acceptor site and is predicted to interfere with normal LDLR mRNA splicing. This variant has not been reported in large, … (more)
This variant disrupts a canonical splice-acceptor site and is predicted to interfere with normal LDLR mRNA splicing. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in several individuals affected with hypercholesterolemia (PMIDs: 12436241 (2002), 25962062 (2015), 33418990 (2021), 34456200 (2021), 35910211 (2022)). Based on the available information, this variant is classified as likely pathogenic. (less)
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Likely Pathogenic
(Dec 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
(Semidominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004827279.1
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.941-2A>G canonical splice site variant in LDLR gene has been identified in at least four individuals who fulfill the clinical criteria of Familial Hypercholesterolemia … (more)
The c.941-2A>G canonical splice site variant in LDLR gene has been identified in at least four individuals who fulfill the clinical criteria of Familial Hypercholesterolemia (FH) (PMID: 12436241, 25962062, 34456200, 33418990). In-silico computational prediction tools suggest that this variant likely leads to acceptor loss (SpliceAI: 0.9934) and disturbs normal splicing, resulting in an aberrant or absence of protein product (PMID: 16199547). Loss-of-function variants in LDLR are known to be pathogenic (PMID: 33740630, 15321837, 20809525, 28645073). Truncating variants downstream of this variant are reported to be pathogenic in the literature (PMID: 16389549, 28008010, 30586733). This variant is absent in the general population database (gnomAD) and interpreted as likely pathogenic/pathogenic by several submitters in the ClinVar database (ClinVar ID: 251554). Therefore, the c.941-2A>G variant in the LDLR gene is classified as likely pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
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Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum
Accession: SCV000606282.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
|
Comment:
Comment:
Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 251554). This variant is also known as IVS6-2A>G. Disruption of this splice site has been observed in individuals with familial hypercholesterolemia (PMID: 12436241, 25962062). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 6 of the LDLR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073).
Comment:
This variant disrupts a canonical splice-acceptor site and is predicted to interfere with normal LDLR mRNA splicing. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in several individuals affected with hypercholesterolemia (PMIDs: 12436241 (2002), 25962062 (2015), 33418990 (2021), 34456200 (2021), 35910211 (2022)). Based on the available information, this variant is classified as likely pathogenic.
Comment:
The c.941-2A>G canonical splice site variant in LDLR gene has been identified in at least four individuals who fulfill the clinical criteria of Familial Hypercholesterolemia (FH) (PMID: 12436241, 25962062, 34456200, 33418990). In-silico computational prediction tools suggest that this variant likely leads to acceptor loss (SpliceAI: 0.9934) and disturbs normal splicing, resulting in an aberrant or absence of protein product (PMID: 16199547). Loss-of-function variants in LDLR are known to be pathogenic (PMID: 33740630, 15321837, 20809525, 28645073). Truncating variants downstream of this variant are reported to be pathogenic in the literature (PMID: 16389549, 28008010, 30586733). This variant is absent in the general population database (gnomAD) and interpreted as likely pathogenic/pathogenic by several submitters in the ClinVar database (ClinVar ID: 251554). Therefore, the c.941-2A>G variant in the LDLR gene is classified as likely pathogenic.
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:
subject mutated among 2600 FH index cases screened = 1 , family member = 1
Comment:
Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 251554). This variant is also known as IVS6-2A>G. Disruption of this splice site has been observed in individuals with familial hypercholesterolemia (PMID: 12436241, 25962062). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 6 of the LDLR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073).
Comment:
This variant disrupts a canonical splice-acceptor site and is predicted to interfere with normal LDLR mRNA splicing. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in several individuals affected with hypercholesterolemia (PMIDs: 12436241 (2002), 25962062 (2015), 33418990 (2021), 34456200 (2021), 35910211 (2022)). Based on the available information, this variant is classified as likely pathogenic.
Comment:
The c.941-2A>G canonical splice site variant in LDLR gene has been identified in at least four individuals who fulfill the clinical criteria of Familial Hypercholesterolemia (FH) (PMID: 12436241, 25962062, 34456200, 33418990). In-silico computational prediction tools suggest that this variant likely leads to acceptor loss (SpliceAI: 0.9934) and disturbs normal splicing, resulting in an aberrant or absence of protein product (PMID: 16199547). Loss-of-function variants in LDLR are known to be pathogenic (PMID: 33740630, 15321837, 20809525, 28645073). Truncating variants downstream of this variant are reported to be pathogenic in the literature (PMID: 16389549, 28008010, 30586733). This variant is absent in the general population database (gnomAD) and interpreted as likely pathogenic/pathogenic by several submitters in the ClinVar database (ClinVar ID: 251554). Therefore, the c.941-2A>G variant in the LDLR gene is classified as likely pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| The Prevalence and Genetic Spectrum of Familial Hypercholesterolemia in Qatar Based on Whole Genome Sequencing of 14,000 Subjects. | Diboun I | Frontiers in genetics | 2022 | PMID: 35910211 |
| 2022 Consensus statement on the management of familial hypercholesterolemia in Korea. | Lee CJ | The Korean journal of internal medicine | 2022 | PMID: 35882565 |
| Phenotypic and Genetic Analyses of Korean Patients with Familial Hypercholesterolemia: Results from the KFH Registry 2020. | Kim H | Journal of atherosclerosis and thrombosis | 2022 | PMID: 34456200 |
| Limited-Variant Screening vs Comprehensive Genetic Testing for Familial Hypercholesterolemia Diagnosis. | Sturm AC | JAMA cardiology | 2021 | PMID: 34037665 |
| Molecular genetic testing for autosomal dominant hypercholesterolemia in 29,449 Norwegian index patients and 14,230 relatives during the years 1993-2020. | Leren TP | Atherosclerosis | 2021 | PMID: 33740630 |
| The LDLR, APOB, and PCSK9 Variants of Index Patients with Familial Hypercholesterolemia in Russia. | Meshkov A | Genes | 2021 | PMID: 33418990 |
| Whole-Genome Sequencing to Characterize Monogenic and Polygenic Contributions in Patients Hospitalized With Early-Onset Myocardial Infarction. | Khera AV | Circulation | 2019 | PMID: 30586733 |
| Analysis of LDLR variants from homozygous FH patients carrying multiple mutations in the LDLR gene. | Jiang L | Atherosclerosis | 2017 | PMID: 28645073 |
| Hypercholesterolemia: The role of PCSK9. | Melendez QM | Archives of biochemistry and biophysics | 2017 | PMID: 28587771 |
| Genetic identification of familial hypercholesterolemia within a single U.S. health care system. | Abul-Husn NS | Science (New York, N.Y.) | 2016 | PMID: 28008010 |
| Genetic testing of Korean familial hypercholesterolemia using whole-exome sequencing. | Han SM | PloS one | 2015 | PMID: 25962062 |
| Mechanistic implications for LDL receptor degradation from the PCSK9/LDLR structure at neutral pH. | Lo Surdo P | EMBO reports | 2011 | PMID: 22081141 |
| Molecular spectrum of autosomal dominant hypercholesterolemia in France. | Marduel M | Human mutation | 2010 | PMID: 20809525 |
| Mutational analysis in UK patients with a clinical diagnosis of familial hypercholesterolaemia: relationship with plasma lipid traits, heart disease risk and utility in relative tracing. | Humphries SE | Journal of molecular medicine (Berlin, Germany) | 2006 | PMID: 16389549 |
| Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
| Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review. | Austin MA | American journal of epidemiology | 2004 | PMID: 15321837 |
| 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 |
| Identification of four novel mutations of the low-density lipoprotein receptor gene in Korean patients with familial hypercholesterolemia. | Shin JA | Clinical genetics | 2000 | PMID: 10782930 |
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Text-mined citations for rs112366278 ...
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.