NC_000019.10:g.11089414C>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 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000238051.24

Allele description [Variation Report for NC_000019.10:g.11089414C>G]

NC_000019.10:g.11089414C>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:

NC_000019.10:g.11089414C>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

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:

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

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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	PubMed (4) [See all records that cite these PMIDs] 1301956, 15241806, 19411563, 20828696 Citation Link,
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	PubMed (2) [See all records that cite these PMIDs] 25741868, 1301956
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	PubMed (1) [See all records that cite this PMID]
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	PubMed (1) [See all records that cite this PMID]
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	PubMed (2) [See all records that cite these PMIDs] 25741868, 1301956
SCV000607394	Fundacion Hipercolesterolemia Familiar - SAFEHEART	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 1, 2016)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 1301956
SCV000748119	Iberoamerican FH Network	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 1, 2016)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 1301956
SCV000915811	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Nov 5, 2018)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 21538688, 15241806, 15523646, 1301956, 19007590, 19411563 Citation Link,
SCV002811144	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 9, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003827091	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 19, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
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	PubMed (11) [See all records that cite these PMIDs] 1301956, 15241806, 18096825, 19007590, 19411563, 21538688, 28475941, 30312929, 31153816, 32660911, 25741868

Help

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.

PubMed [citation]

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.

PubMed [citation]

PMID:: 15523646

See all PubMed Citations (13)

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

"Homozygous patient fibroblasts, 125I-LDL assays"

PubMed [ID: 1301956]

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, 1186â€“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

"Assay description:Hmz patient fibroblasts, 125I-LDL assays"

PubMed [ID: 1301956]

#	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

"Hmz patient fibroblasts, 125I-LDL assays"

PubMed [ID: 1301956]

#	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

"Assay Description:Hmz patient fibroblasts, 125I-LDL assays"

PubMed [ID: 1301956]

#	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: Nov 18, 2024

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