Submissions for variant NC_000019.10:g.11089414C>G

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000238051	SCV000294393	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000238051	SCV000322868	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research	0/190 non-FH alleles
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000238051	SCV000503088	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	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
Labcorp Genetics (formerly Invitae), Labcorp	RCV001034639	SCV000544670	pathogenic	Familial hypercholesterolemia	2024-12-07	criteria provided, single submitter	clinical testing	This variant occurs in a non-coding region of the LDLR gene. It does not change the encoded amino acid sequence of the LDLR protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with familial hypercholesterolemia or mixed hyperlipidemia (PMID: 1301956, 15241806, 18096825, 19007590, 19411563). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. This variant is also known as c.-42C>G and FH Columbia-2. ClinVar contains an entry for this variant (Variation ID: 250956). Studies have shown that this variant alters LDLR gene expression (PMID: 19411563, 21538688). For these reasons, this variant has been classified as Pathogenic.
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000238051	SCV000583619	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing	ACMG Guidelines: Pathogenic (ii)
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000238051	SCV000588476	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Fundacion Hipercolesterolemia Familiar	RCV000238051	SCV000607394	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Iberoamerican FH Network	RCV000238051	SCV000748119	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Illumina Laboratory Services, Illumina	RCV000238051	SCV000915811	pathogenic	Hypercholesterolemia, familial, 1	2018-11-05	criteria provided, single submitter	clinical testing	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.
Color Diagnostics, LLC DBA Color Health	RCV001034639	SCV001734616	likely pathogenic	Familial hypercholesterolemia	2023-11-16	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV002379056	SCV002697540	likely pathogenic	Cardiovascular phenotype	2024-02-16	criteria provided, single submitter	clinical testing	The c.-135C>G variant is located in the 5' untranslated region (5’ UTR) of the LDLR gene. This variant results from a C to G substitution 135 bases upstream from the first translated codon. This variant, also described as c.-42C>G and FH Columbia-2, has been reported in multiple individuals with hypercholesterolemia (FH), including at least one homozygote (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Mozas P et al. Hum. Mutat., 2004 Aug;24:187; Civeira F et al. J. Am. Coll. Cardiol., 2008 Nov;52:1546-53; Bourbon M et al. J. Med. Genet., 2009 May;46:352-7; Sánchez-Hernández RM et al. J Clin Lipidol, 2019 May;13:618-626; Rimbert A et al. Front Genet, 2021 Jan;12:809256; Arrobas Velilla T et al. Front Genet, 2022 Aug;13:971651; Marco-Benedí V et al. Atherosclerosis, 2022 May;349:211-218). Functional studies demonstrated significantly reduced LDLR activity in cells with this variant (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; De Castro-Orós I et al. Hum. Mutat., 2011 Aug;32:868-72). RNA analysis in heterozygote carriers suggested lack of transcription of the mutant allele; however, the possible influence of additional LDLR variants in cis could not be excluded (Bourbon M et al. J. Med. Genet., 2009 May;46:352-7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000238051	SCV002811144	pathogenic	Hypercholesterolemia, familial, 1	2021-09-09	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000238051	SCV003827091	pathogenic	Hypercholesterolemia, familial, 1	2022-10-19	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000238051	SCV004839110	likely pathogenic	Hypercholesterolemia, familial, 1	2024-01-08	criteria provided, single submitter	clinical testing	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.
Natera, Inc.	RCV001034639	SCV001456134	pathogenic	Familial hypercholesterolemia	2020-09-16	no assertion criteria provided	clinical testing