ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.68-1G>C
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.68-1G>C
Variation ID: 251005 Accession: VCV000251005.7
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11100222 (GRCh38) [ NCBI UCSC ] 19: 11210898 (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 Sep 9, 2017 May 1, 2024 Nov 28, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000527.5:c.68-1G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NM_001195798.2:c.68-1G>C splice acceptor NM_001195799.2:c.68-1G>C splice acceptor NM_001195800.2:c.68-1G>C splice acceptor NM_001195803.2:c.68-1G>C splice acceptor NM_001406861.1:c.326-1G>C splice acceptor NC_000019.10:g.11100222G>C NC_000019.9:g.11210898G>C NG_009060.1:g.15842G>C LRG_274:g.15842G>C LRG_274t1:c.68-1G>C - Protein change
- Other names
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- Canonical SPDI
- NC_000019.10:11100221:G:C
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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
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
4064 | 4339 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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 (2) |
criteria provided, multiple submitters, no conflicts
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Mar 25, 2016 | RCV000238079.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 23, 2017 | RCV000521979.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 21, 2018 | RCV002365237.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 28, 2023 | RCV002519837.2 |
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
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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
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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
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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)
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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: SCV000294449.2
First in ClinVar: Jul 29, 2016 Last updated: Sep 09, 2017 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 1
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Pathogenic
(Mar 01, 2016)
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criteria provided, single submitter
Method: curation, literature only
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Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown, not applicable
Allele origin:
germline,
not applicable
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Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge
Accession: SCV000599310.1
First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017 |
Observation 1: Observation 2:
Comment on evidence:
Assay Description:Hmz patients' fibroblasts, RNA assays / 125I-LDL and ligand-binding assays
Result:
skipping of the first 10 nts from exon 2 (p.Val23Aspfs*180) / 8% LDL-LDLR binding, LDLR not detected at cell surface
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Pathogenic
(Oct 23, 2017)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000617498.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
Comment:
The c.68-1 G>C variant in the LDLR gene has been identified in a homozygous state in one individual with severe hypercholesterolemia and tendon xnathomas. Three … (more)
The c.68-1 G>C variant in the LDLR gene has been identified in a homozygous state in one individual with severe hypercholesterolemia and tendon xnathomas. Three maternal relatives were heterozygous for the variant and had serum choleterol levels consistent with heterozygous FH (HeFH). Cultured fibroblasts from the proband showed null LDLR protein synthesis. Additionally, functional mRNA studies supported destruction of the canonical splice acceptor site in intron 1, and utilization of a cryptic acceptor site downstream of exon 2 (Maruyama et al. 1998). This variant was also published in an individual with clinical HeFH, who also harbored a rare variant in the PCSK9 gene (Ohta et al., 2016). This variant is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Other splice site variants in the LDLR gene, including c.68-2 A>T and c.68-2 A>G, have been reported in HGMD in association with FH (Stenson et al., 2014). Furthermore, the c.68-1 G>C variant is not observed in large population cohorts (Lek et al., 2016). (less)
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Pathogenic
(Nov 28, 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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Invitae
Accession: SCV003256922.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects an acceptor splice site in intron 1 of the LDLR gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects an acceptor splice site in intron 1 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 not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with familial hypercholesterolemia (PMID: 10200052; Invitae). ClinVar contains an entry for this variant (Variation ID: 251005). 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)
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Pathogenic
(Jun 21, 2018)
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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: SCV002664186.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.68-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 2 of the LDLR gene, and is … (more)
The c.68-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 2 of the LDLR gene, and is located in the region of the ligand binding 1 domain. This variant has been reported in a homozygous Japanese female from consanguineous parents, who had hypercholesterolemia and tendon xanthomas, as well as in an Italian family with heterozygous familial hypercholesterolemia, and in a Japanese female with hypercholesterolemia who also harbored a PCSK9 variant (Maruyama T et al. Hum. Mutat., 1998;11:480-1; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Ohta N et al. J Clin Lipidol 2016 Jan;10:547-555.e5). Limited functional studies in fibroblasts from the homozygous individual reportedly showed no LDLR protein was produced, while RNA studies suggested use of a downstream cryptic acceptor site caused a frameshift leading to a premature stop codon (Maruyama T et al. Hum. Mutat., 1998;11:480-1). 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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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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Analysis of LDLR variants from homozygous FH patients carrying multiple mutations in the LDLR gene. | Jiang L | Atherosclerosis | 2017 | PMID: 28645073 |
Proprotein convertase subtilisin/kexin 9 V4I variant with LDLR mutations modifies the phenotype of familial hypercholesterolemia. | Ohta N | Journal of clinical lipidology | 2016 | PMID: 27206942 |
Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. | Bertolini S | Atherosclerosis | 2013 | PMID: 23375686 |
Molecular spectrum of autosomal dominant hypercholesterolemia in France. | Marduel M | Human mutation | 2010 | PMID: 20809525 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
A novel point mutation in a splice acceptor site of intron 1 of the human low density lipoprotein receptor gene which causes severe hypercholesterolemia: an unexpected absence of exon skipping. Mutations in brief no. 139. Online. | Maruyama T | Human mutation | 1998 | PMID: 10200052 |
Text-mined citations for rs879254397 ...
HelpRecord last updated Sep 01, 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.