ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.1358+1G>A
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000527.5(LDLR):c.1358+1G>A
Variation ID: 251802 Accession: VCV000251802.5
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11113450 (GRCh38) [ NCBI UCSC ] 19: 11224126 (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 Dec 17, 2016 Apr 20, 2024 May 19, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000527.5:c.1358+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001195798.2:c.1358+1G>A splice donor NM_001195799.2:c.1235+1G>A splice donor NM_001195800.2:c.854+1G>A splice donor NM_001195803.2:c.977+1G>A splice donor NC_000019.10:g.11113450G>A NC_000019.9:g.11224126G>A NG_009060.1:g.29070G>A LRG_274:g.29070G>A LRG_274t1:c.1358+1G>A - Protein change
- Other names
- IVS9 ds G-A +1
- Canonical SPDI
- NC_000019.10:11113449: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.
Exome Aggregation Consortium (ExAC) 0.00001
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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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. |
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Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Mar 30, 2017 | RCV000237640.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 2, 2021 | RCV002479949.1 | |
Pathogenic (1) |
criteria provided, single submitter
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May 19, 2023 | RCV003581623.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 22, 2019 | RCV004017556.1 |
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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Likely 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
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LDLR-LOVD, British Heart Foundation
Accession: SCV000295382.2
First in ClinVar: Jul 29, 2016 Last updated: May 03, 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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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Robarts Research Institute, Western University
Accession: SCV000484786.1
First in ClinVar: Dec 17, 2016 Last updated: Dec 17, 2016 |
Number of individuals with the variant: 2
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Pathogenic
(Dec 16, 2016)
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criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
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Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix
Accession: SCV000503339.1
First in ClinVar: Dec 17, 2016 Last updated: Dec 17, 2016 |
Comment:
subject mutated among 2600 FH index cases screened = 1
Number of individuals with the variant: 1
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Pathogenic
(Mar 30, 2017)
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criteria provided, single submitter
Method: clinical testing
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Familial Hypercholesterolemia
Affected status: yes
Allele origin:
germline
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U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille
Accession: SCV000583824.1
First in ClinVar: Dec 17, 2016 Last updated: Dec 17, 2016
Comment:
ACMG Guidelines: Pathogenic (i)
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Number of individuals with the variant: 3
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: SCV000607590.1 First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
Observation 1:
Comment on evidence:
%MAF(ExAC):0.0008276
Observation 2:
Comment on evidence:
Htz patients' Epstein Barr virus transformed lymphocytes, RNA assays
Result:
mutant mR degraded (20% of total)
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Pathogenic
(Aug 02, 2021)
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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: SCV002774353.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
This variant is located in a canonical splice-donor site and interferes with normal LDLR mRNA splicing. The variant has been reported in individuals affected with … (more)
This variant is located in a canonical splice-donor site and interferes with normal LDLR mRNA splicing. The variant has been reported in individuals affected with Familial Hypercholesteremia (FH) in the published literature (PMID: 24632281 (2014), 22390909 (2012), 19208450 (2009), 16627557 (2006), 15701167 (2005), 15241806 (2004)). Therefore, the variant is classified as pathogenic. (less)
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Pathogenic
(May 19, 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: SCV004298356.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this … (more)
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 251802). This variant is also known as IVS9+1G>A. Disruption of this splice site has been observed in individuals with familial hypercholesterolemia (PMID: 8314561, 15701167, 18096825). This variant is present in population databases (rs775924858, gnomAD 0.0009%). This sequence change affects a donor splice site in intron 9 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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Pathogenic
(Apr 22, 2019)
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criteria provided, single submitter
Method: clinical testing
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Homozygous familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004847714.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The c.1358+1G>A variant in LDLR has been reported in at least 10 individuals with familial hypercholesterolemia (FH) and segregated with disease in 1 affected relative … (more)
The c.1358+1G>A variant in LDLR has been reported in at least 10 individuals with familial hypercholesterolemia (FH) and segregated with disease in 1 affected relative from 1 family (Top 1993, Mozas 2004, Zakharova 2005, ClinVar submission accessions: SCV000484786.1, SCV000503339.1, SCV000583824.1). It was absent from large population studies. This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. 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, PS4_Moderate. (less)
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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: SCV000606404.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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The LDLR, APOB, and PCSK9 Variants of Index Patients with Familial Hypercholesterolemia in Russia. | Meshkov A | Genes | 2021 | PMID: 33418990 |
Analysis of LDLR variants from homozygous FH patients carrying multiple mutations in the LDLR gene. | Jiang L | Atherosclerosis | 2017 | PMID: 28645073 |
Lipoprotein(a) levels in familial hypercholesterolemia: an important predictor of cardiovascular disease independent of the type of LDL receptor mutation. | Alonso R | Journal of the American College of Cardiology | 2014 | PMID: 24632281 |
Cardiovascular risk in relation to functionality of sequence variants in the gene coding for the low-density lipoprotein receptor: a study among 29,365 individuals tested for 64 specific low-density lipoprotein-receptor sequence variants. | Huijgen R | European heart journal | 2012 | PMID: 22390909 |
Molecular spectrum of autosomal dominant hypercholesterolemia in France. | Marduel M | Human mutation | 2010 | PMID: 20809525 |
Effects of intronic mutations in the LDLR gene on pre-mRNA splicing: Comparison of wet-lab and bioinformatics analyses. | Holla ØL | Molecular genetics and metabolism | 2009 | PMID: 19208450 |
Femoral atherosclerosis in heterozygous familial hypercholesterolemia: influence of the genetic defect. | Junyent M | Arteriosclerosis, thrombosis, and vascular biology | 2008 | PMID: 18096825 |
Analysis of sequence variations in the LDL receptor gene in Spain: general gene screening or search for specific alterations? | Blesa S | Clinical chemistry | 2006 | PMID: 16627557 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Familial hypercholesterolemia in St-Petersburg: the known and novel mutations found in the low density lipoprotein receptor gene in Russia. | Zakharova FM | BMC medical genetics | 2005 | PMID: 15701167 |
Molecular characterization of familial hypercholesterolemia in Spain: identification of 39 novel and 77 recurrent mutations in LDLR. | Mozas P | Human mutation | 2004 | PMID: 15241806 |
Identification of a splice-site mutation in the low density lipoprotein receptor gene by denaturing gradient gel electrophoresis. | Top B | Human genetics | 1993 | PMID: 8314561 |
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Text-mined citations for rs775924858 ...
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.