subject mutated among 2600 FH index cases screened = 1
ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.1705+1G>T
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic/Likely pathogenic
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
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NM_000527.5(LDLR):c.1705+1G>T
Variation ID: 251981 Accession: VCV000251981.6
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11116213 (GRCh38) [ NCBI UCSC ] 19: 11226889 (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 Nov 24, 2024 Aug 29, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.1705+1G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001195798.2:c.1705+1G>T splice donor NM_001195799.2:c.1582+1G>T splice donor NM_001195800.2:c.1201+1G>T splice donor NM_001195803.2:c.1324+1G>T splice donor NC_000019.10:g.11116213G>T NC_000019.9:g.11226889G>T NG_009060.1:g.31833G>T LRG_274:g.31833G>T LRG_274t1:c.1705+1G>T - Protein change
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- Other names
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- Canonical SPDI
- NC_000019.10:11116212:G: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. |
|||
| LDLR | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
4225 | 4527 | |
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 (5) |
criteria provided, multiple submitters, no conflicts
|
Jan 30, 2020 | RCV000237724.7 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 29, 2023 | RCV004701339.2 |
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
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)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: literature only
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Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
LDLR-LOVD, British Heart Foundation
Accession: SCV000295593.2
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
|
|
|
Pathogenic
(Dec 16, 2016)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
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: SCV000503392.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Comment:
subject mutated among 2600 FH index cases screened = 1
Number of individuals with the variant: 1
|
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Pathogenic
(Mar 01, 2016)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: curation, literature only
|
Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: not applicable, unknown
Allele origin:
germline,
not applicable
|
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge
Accession: SCV000599384.1
First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017 |
Observation 1: Observation 2:
Comment on evidence:
Assay Description:Htz patients' fibroblasts, RNA (quantification and RT-PCR) assays / Htz patients' Epstein Barr virus transformed lymphocytes, RNA assays / Htz patients' lymphocytes, FACS assays
Result:
skipping of exons 11 and 12 (p.Phe530Thrfs*49) or retention of intron 11 (p.Asp569Glyfs*34) / skipping of exon 11 (p.Phe530Serfs*10) or exons 11 and 12 (p.Phe530Thrfs*49), mutant mRNA degraded (30-40% of total) / 45% cell surface LDLR; 65% LDL-LDLR uptake
|
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Pathogenic
(Jan 30, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
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Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001366193.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PS3,PM2.
|
|
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Pathogenic
(Jul 19, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV005201890.1
First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
Comment:
Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; … (more)
Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 7635482, 33955087, 33740630) (less)
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Pathogenic
(Aug 29, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV005413318.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
PM2, PS3_moderate, PS4_moderate, PVS1
Number of individuals with the variant: 1
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Pathogenic
(-)
N
Not contributing to aggregate classification
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no assertion criteria provided
Method: research
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Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum
Accession: SCV000606490.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
|
Comment:
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PS3,PM2.
Comment:
Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 7635482, 33955087, 33740630)
Comment:
PM2, PS3_moderate, PS4_moderate, PVS1
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
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PS3,PM2.
Comment:
Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 7635482, 33955087, 33740630)
Comment:
PM2, PS3_moderate, PS4_moderate, PVS1
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Founder effects facilitate the use of a genotyping-based approach to molecular diagnosis in Swedish patients with familial hypercholesterolaemia. | Benedek P | Journal of internal medicine | 2021 | PMID: 33955087 |
| 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 |
| Molecular genetic analysis of 1053 Danish individuals with clinical signs of familial hypercholesterolemia. | Brusgaard K | Clinical genetics | 2006 | PMID: 16542394 |
| The relationship of molecular genetic to clinical diagnosis of familial hypercholesterolemia in a Danish population. | Damgaard D | Atherosclerosis | 2005 | PMID: 15823288 |
| Eight novel mutations and functional impairments of the LDL receptor in familial hypercholesterolemia in the north of Japan. | Hattori H | Journal of human genetics | 2002 | PMID: 11916007 |
| Mutant transcripts of the LDL receptor gene: mRNA structure and quantity. | Rødningen OK | Human mutation | 1999 | PMID: 10090473 |
| Two novel point mutations in the EGF precursor homology domain of the LDL receptor gene causing familial hypercholesterolemia. | Leren TP | Human genetics | 1995 | PMID: 7635482 |
Text-mined citations for rs875989926 ...
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 Jan 13, 2025
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.