ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.-135C>G (rs879254375)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000238051 SCV000322868 likely pathogenic Familial hypercholesterolemia 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 Familial hypercholesterolemia 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
Fundacion Hipercolesterolemia Familiar RCV000238051 SCV000607394 likely pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Iberoamerican FH Network RCV000238051 SCV000748119 likely pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Illumina Clinical Services Laboratory,Illumina RCV000238051 SCV000915811 pathogenic Familial hypercholesterolemia 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.
Invitae RCV000238051 SCV000544670 pathogenic Familial hypercholesterolemia 2017-09-14 criteria provided, single submitter clinical testing This sequence change falls in the 5'UTR of the LDLR gene. It does not change the encoded amino acid sequence of the LDLR protein, but has been reported to affect transcription. This variant has been reported in individuals affected with familial hypercholesterolemia or mixed hyperlipidemia (PMID: 15241806, 18096825, 19007590, 19411563, 1301956). ClinVar contains an entry for this variant (Variation ID: 250956). This variant is also known as c.-42C>G in the literature. Experimental studies have shown that this 5' UTR change results in reduced promoter activity, a decrease in LDLR activity and transcription of only one allele (PMID: 21538688, 19411563). In summary, this variant is a promoter region variant that it is reported to reduce promoter activity and decrease LDLR activity and it has been reported in individuals with mixed hyperlipidemia and familial hypercholesterolemia. However, its prevalence in the population is unknown. For these reasons, this variant has been classified as Pathogenic.
LDLR-LOVD, British Heart Foundation RCV000238051 SCV000294393 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000238051 SCV000588476 likely pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000238051 SCV000583619 pathogenic Familial hypercholesterolemia 2017-03-30 criteria provided, single submitter clinical testing ACMG Guidelines: Pathogenic (ii)

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