- This record was updated by the submitter. Please see the current version.
NM_000527.4(LDLR):c.-135C>G AND Hypercholesterolemia, familial, 1
- Germline classification:
- Pathogenic/Likely pathogenic (11 submissions)
- Last evaluated:
- Jan 8, 2024
- Review status:
- 2 stars out of maximum of 4 starscriteria provided, multiple submitters, no conflicts
- Somatic classification
of clinical impact: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Somatic classification
of oncogenicity: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Record status:
- current
- Accession:
- RCV000238051.22
Allele description
NM_000527.4(LDLR):c.-135C>G
- Genes:
- LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]
LDLR-AS1:LDLR antisense RNA 1 [Gene - HGNC] - Variant type:
- single nucleotide variant
- Cytogenetic location:
- 19p13.2
- Genomic location:
- Preferred name:
- NM_000527.4(LDLR):c.-135C>G
- Other names:
- FH Columbia-2
- HGVS:
- NC_000019.10:g.11089414C>G
- NG_009060.1:g.5034C>G
- NM_000527.4:c.-135C>G
- NM_001195798.1:c.-135C>G
- NM_001195799.1:c.-135C>G
- NM_001195800.1:c.-135C>G
- NM_001195803.1:c.-135C>G
- LRG_274t1:c.-135C>G
- LRG_274:g.5034C>G
- NC_000019.9:g.11200090C>G
- NR_163945.1:n.246G>C
- c.-135C>G
This HGVS expression did not pass validation- Links:
- LDLR-LOVD, British Heart Foundation: LDLR_000003;
- Molecular consequence:
- NR_163945.1:n.246G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
- Observations:
- 1
Condition(s)
- Name:
- Hypercholesterolemia, familial, 1
- Synonyms:
- LDL RECEPTOR DISORDER; Hyperlipoproteinemia Type IIa; HYPER-LOW-DENSITY-LIPOPROTEINEMIA; See all synonyms [MedGen]
- Identifiers:
- MONDO: MONDO:0007750; MedGen: C0745103; Orphanet: 391665; OMIM: 143890
Assertion and evidence details
Submission Accession | Submitter | Review Status (Assertion method) | Clinical Significance (Last evaluated) | Origin | Method | Citations |
---|---|---|---|---|---|---|
SCV000294393 | LDLR-LOVD, British Heart Foundation | criteria provided, single submitter (ACGS Guidelines, 2013) | Likely pathogenic (Mar 25, 2016) | germline | literature only | |
SCV000322868 | Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge | criteria provided, single submitter (ACMG Guidelines, 2015) | Likely pathogenic (Mar 1, 2016) | germline | research | |
SCV000503088 | Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix | criteria provided, single submitter (ACMG Guidelines, 2015) | Likely pathogenic (Dec 16, 2016) | germline | clinical testing | |
SCV000583619 | U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Mar 30, 2017) | germline | clinical testing | |
SCV000588476 | Laboratory of Genetics and Molecular Cardiology, University of São Paulo - HipercolBrasil | criteria provided, single submitter (ACMG Guidelines, 2015) | Likely pathogenic (Mar 1, 2016) | germline | research | |
SCV000607394 | Fundacion Hipercolesterolemia Familiar - SAFEHEART | criteria provided, single submitter (ACMG Guidelines, 2015) | Likely pathogenic (Mar 1, 2016) | germline | research | |
SCV000748119 | Iberoamerican FH Network | criteria provided, single submitter (ACMG Guidelines, 2015) | Likely pathogenic (Mar 1, 2016) | germline | research | |
SCV000915811 | Illumina Laboratory Services, Illumina | criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) | Pathogenic (Nov 5, 2018) | germline | clinical testing | |
SCV002811144 | Fulgent Genetics, Fulgent Genetics | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Sep 9, 2021) | unknown | clinical testing | |
SCV003827091 | Revvity Omics, Revvity | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Oct 19, 2022) | germline | clinical testing | |
SCV004839110 | All of Us Research Program, National Institutes of Health | criteria provided, single submitter (ACMG Guidelines, 2015) | Likely Pathogenic (Jan 8, 2024) | germline | clinical testing |
Summary from all submissions
Ethnicity | Origin | Affected | Individuals | Families | Chromosomes tested | Number Tested | Family history | Method |
---|---|---|---|---|---|---|---|---|
not provided | germline | yes | 6 | 1 | not provided | 2604 | not provided | clinical testing, research, literature only |
not provided | germline | unknown | 1 | not provided | not provided | 108544 | not provided | clinical testing, research |
not provided | unknown | unknown | not provided | not provided | not provided | not provided | not provided | clinical testing |
Citations
PubMed
Update of the Portuguese Familial Hypercholesterolaemia Study.
Medeiros AM, Alves AC, Francisco V, Bourbon M; investigators of the Portuguese FH Study..
Atherosclerosis. 2010 Oct;212(2):553-8. doi: 10.1016/j.atherosclerosis.2010.07.012. Epub 2010 Aug 8.
- PMID:
- 20828696
LDL-receptor mutations in Europe.
Dedoussis GV, Schmidt H, Genschel J.
Hum Mutat. 2004 Dec;24(6):443-59. Review. Erratum in: Hum Mutat. 2005 Sep;26(3):277-8.
- PMID:
- 15523646
Details of each submission
From LDLR-LOVD, British Heart Foundation, SCV000294393.2
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | 1 | not provided | not provided | literature only | PubMed (4) |
2 | not provided | 1 | not provided | not provided | literature only | PubMed (4) |
3 | not provided | 1 | not provided | not provided | literature only | PubMed (4) |
4 | not provided | 1 | not provided | not provided | literature only | PubMed (4) |
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | yes | 1 | not provided | not provided | 1 | not provided | not provided | not provided | |
2 | germline | yes | 1 | not provided | not provided | 1 | not provided | not provided | not provided | |
3 | germline | yes | 1 | not provided | not provided | 1 | not provided | not provided | not provided | |
4 | germline | yes | 1 | not provided | not provided | 1 | not provided | not provided | not provided |
From Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, SCV000322868.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | research | PubMed (2) |
2 | not provided | not provided | not provided | not provided | research | PubMed (2) |
Description
Description
0/190 non-FH alleles
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
2 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix, SCV000503088.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | 1 | not provided | not provided | clinical testing | PubMed (1) |
Description
subject mutated among 2600 FH index cases screened = 1 / located in putative cis acting transcription site, Sp1, AJP Smith et al, European Journal of Human Genetics (2007) 15, 1186–1189
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | yes | 2600 | not provided | not provided | 1 | not provided | not provided | not provided |
From U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, SCV000583619.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | 1 | not provided | not provided | clinical testing | PubMed (1) |
Description
Dutch Lipid Clinic Scoring : Definite FH
Description
ACMG Guidelines: Pathogenic (ii)
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | yes | not provided | not provided | not provided | 1 | not provided | 1 | not provided |
From Laboratory of Genetics and Molecular Cardiology, University of São Paulo - HipercolBrasil, SCV000588476.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | research | PubMed (2) |
2 | not provided | not provided | not provided | not provided | research | PubMed (2) |
Description
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
2 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Fundacion Hipercolesterolemia Familiar - SAFEHEART, SCV000607394.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | research | PubMed (2) |
2 | not provided | not provided | not provided | not provided | research | PubMed (2) |
Description
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
2 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Iberoamerican FH Network, SCV000748119.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | research | PubMed (2) |
2 | not provided | not provided | not provided | not provided | research | PubMed (2) |
Description
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
2 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Illumina Laboratory Services, Illumina, SCV000915811.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (6) |
Description
The LDLR c.-135C>G variant has been reported in four studies and was found in a total of ten individuals with familial hypercholesterolemia (FH) including one in a homozygous state and nine in a heterozygous state (Hobbs et al. 1992; Mozas et al. 2004; Civeira et al. 2008; Bourbon et al. 2009). An additional study detected the variant at a frequency of 1.33% in 1,636 probands with a positive diagnosis of FH (De Castro-Oros et al. 2011). The c.-135C>G variant was absent from 300 control alleles and is not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium, or the Genome Aggregation Database. Functional studies demonstrated that the variant resulted in between 5-15% of LDL receptor activity (Hobbs et al. 1992; De Castro-Oros et al. 2011). The variant lies in an SP1 binding site in the promoter of the LDLR gene (Hobbs te al. 1992; Dedoussis et al. 2004). Based on the evidence, the c.-135C>G variant is classified as pathogenic for familial hypercholesterolemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Fulgent Genetics, Fulgent Genetics, SCV002811144.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | unknown | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Revvity Omics, Revvity, SCV003827091.2
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From All of Us Research Program, National Institutes of Health, SCV004839110.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | 1 | not provided | not provided | clinical testing | PubMed (11) |
Description
This missense variant causes a C to G nucleotide substitution at position -135 in the promoter region of the SP1 binding motif in the LDLR gene. This variant is also known as c.-42C>G and FH Columbia-2 in the literature. Functional studies have shown that this variant causes a significant decrease in LDLR promoter activity (PMID: 21538688), and that the mutant protein shows a significant reduction in LDLR activity (PMID: 1301956). This variant has been reported in more than 10 individuals affected with familial hypercholesterolemia (PMID: 1301956, 15241806, 18096825, 19007590, 19411563, 28475941, 30312929, 31153816, 32660911; Stoll et al. 2018). It has been shown that this variant segregates with disease in three affected individuals from one family (PMID: 19411563). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | unknown | 108544 | not provided | not provided | 1 | not provided | not provided | not provided |
Last Updated: May 1, 2024
PubMed [ID: 1301956]