subject mutated among 2600 FH index cases screened = 1
NM_000527.5(LDLR):c.1845+2T>C
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic/Likely pathogenic
Pathogenic (5); Likely pathogenic (1)
Pathogenic (5); Likely pathogenic (1)
6 out of 7 submissions contributed to this 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
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000527.5(LDLR):c.1845+2T>C
Variation ID: 252070 Accession: VCV000252070.11
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19p13.2 19: 11117000 (GRCh38) [ NCBI UCSC ] 19: 11227676 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 15, 2026 Nov 25, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.1845+2T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001195798.2:c.1845+2T>C splice donor NM_001195799.2:c.1722+2T>C splice donor NM_001195800.2:c.1341+2T>C splice donor NM_001195803.2:c.1464+2T>C splice donor NC_000019.10:g.11117000T>C NC_000019.9:g.11227676T>C NG_009060.1:g.32620T>C LRG_274:g.32620T>C LRG_274t1:c.1845+2T>C - Protein change
- -
- Other names
-
FH Niigata
- Canonical SPDI
- NC_000019.10:11116999:T:C
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
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. |
|||
| LDLR | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
4565 | 4906 | |
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/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Dec 16, 2016 | RCV000237150.5 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 11, 2023 | RCV000819649.7 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 25, 2024 | RCV002411097.3 |
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. |
Expand all rows
Collapse all rows
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Mar 25, 2016)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Familial hypercholesterolemia
(Autosomal dominant inheritance)
|
LDLR-LOVD, British Heart Foundation
Accession: SCV000295701.2
First in ClinVar: Jul 29, 2016 Last updated: May 03, 2018 |
Observation 1
Collection method: literature only
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Dec 16, 2016)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hypercholesterolemia, familial, 1 |
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix
Accession: SCV000503424.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Mar 01, 2016)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Familial hypercholesterolemia
(Autosomal dominant inheritance)
|
Laboratory of Genetics and Molecular Cardiology, University of São Paulo
Study: HipercolBrasil
Accession: SCV000588613.1 First in ClinVar: Aug 13, 2017 Last updated: Aug 13, 2017 |
Observation:
2
Observation 1
Collection method: research
Allele origin: germline
Affected status: unknown
Comment on evidence:
%MAF(ExAC):0.0008237
Observation 2
Collection method: research
Allele origin: germline
Affected status: unknown
Comment on evidence:
Assay description:Hmz patients' fibroblasts, 125I-LDL assays
Result:
<2% LDLR activity; generates 8,4kb and 5,3kb mRNAs
|
|
|
Pathogenic
(Nov 01, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Familial hypercholesterolemia |
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002041586.1
First in ClinVar: Dec 25, 2021 Last updated: Dec 25, 2021 |
Comment:
show
Variant summary: LDLR c.1845+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5` splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251462 control chromosomes (gnomAD). c.1845+2T>C has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (e.g. Maruyama_1995, Hori_2019, Tada_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=3) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Nov 25, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Cardiovascular phenotype |
Ambry Genetics
Accession: SCV002717069.3
First in ClinVar: Nov 29, 2022 Last updated: Jan 13, 2025 |
Comment:
show
The c.1845+2T>C intronic pathogenic mutation results from a T to C substitution two nucleotides after coding exon 12 in the LDLR gene. This variant (also referred to as FH Niigata) was reported in individual(s) with features consistent with familial hypercholesterolemia (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Maruyama T et al. Arterioscler. Thromb. Vasc. Biol., 1995 Oct;15:1713-8; Funahashi T et al. J. Intern. Med., 1996 Feb;239:187-90; Miyake Y et al. Atherosclerosis, 2009 Mar;203:153-60; Tada H et al. J Clin Lipidol, 2018 Dec;12:397-402.e2). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Oct 11, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Familial hypercholesterolemia |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000960320.5
First in ClinVar: Aug 14, 2019 Last updated: Feb 15, 2026 |
Comment:
show
This sequence change affects a donor splice site in intron 12 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). This variant is present in population databases (rs778408161, gnomAD 0.0009%). Disruption of this splice site has been observed in individuals with hypercholesterolemia (PMID: 7583548, 26927322). ClinVar contains an entry for this variant (Variation ID: 252070). 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. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Familial hypercholesterolemia |
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum
Accession: SCV000606538.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
Observation: 1
Collection method: research
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: research
Allele origin: germline
Affected status: unknown
|
|
Comment:
Comment:
Variant summary: LDLR c.1845+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5` splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251462 control chromosomes (gnomAD). c.1845+2T>C has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (e.g. Maruyama_1995, Hori_2019, Tada_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=3) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The c.1845+2T>C intronic pathogenic mutation results from a T to C substitution two nucleotides after coding exon 12 in the LDLR gene. This variant (also referred to as FH Niigata) was reported in individual(s) with features consistent with familial hypercholesterolemia (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Maruyama T et al. Arterioscler. Thromb. Vasc. Biol., 1995 Oct;15:1713-8; Funahashi T et al. J. Intern. Med., 1996 Feb;239:187-90; Miyake Y et al. Atherosclerosis, 2009 Mar;203:153-60; Tada H et al. J Clin Lipidol, 2018 Dec;12:397-402.e2). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Comment:
This sequence change affects a donor splice site in intron 12 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). This variant is present in population databases (rs778408161, gnomAD 0.0009%). Disruption of this splice site has been observed in individuals with hypercholesterolemia (PMID: 7583548, 26927322). ClinVar contains an entry for this variant (Variation ID: 252070). 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| A catalog of the pathogenic mutations of LDL receptor gene in Japanese familial hypercholesterolemia. | Tada H | Journal of clinical lipidology | 2020 | PMID: 32331935 |
| Impact of LDLR and PCSK9 pathogenic variants in Japanese heterozygous familial hypercholesterolemia patients. | Hori M | Atherosclerosis | 2019 | PMID: 31491741 |
| Assessment of arterial stiffness in patients with familial hypercholesterolemia. | Tada H | Journal of clinical lipidology | 2018 | PMID: 29292049 |
| Analysis of LDLR variants from homozygous FH patients carrying multiple mutations in the LDLR gene. | Jiang L | Atherosclerosis | 2017 | PMID: 28645073 |
| Molecular analysis of the LDLR gene in coronary artery disease patients from the Indian population. | ArulJothi KN | Clinical biochemistry | 2016 | PMID: 26927322 |
| Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. | Do R | Nature | 2015 | PMID: 25487149 |
| Molecular spectrum of autosomal dominant hypercholesterolemia in France. | Marduel M | Human mutation | 2010 | PMID: 20809525 |
| Update of Japanese common LDLR gene mutations and their phenotypes: Mild type mutation L547V might predominate in the Japanese population. | Miyake Y | Atherosclerosis | 2009 | PMID: 18718593 |
| Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
| A compound heterozygote for familial hypercholesterolaemia with a homozygous mother. | Funahashi T | Journal of internal medicine | 1996 | PMID: 8568489 |
| Common mutations in the low-density-lipoprotein-receptor gene causing familial hypercholesterolemia in the Japanese population. | Maruyama T | Arteriosclerosis, thrombosis, and vascular biology | 1995 | PMID: 7583548 |
| Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. | Hobbs HH | Human mutation | 1992 | PMID: 1301956 |
| Multiple crm- mutations in familial hypercholesterolemia. Evidence for 13 alleles, including four deletions. | Hobbs HH | The Journal of clinical investigation | 1988 | PMID: 3343347 |
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Text-mined citations for rs778408161 ...
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 Apr 13, 2026
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.