ClinVar Genomic variation as it relates to human health

0/190 non-FH alleles

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

ACMG Guidelines: Pathogenic (ii)

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.

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.

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). 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.

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.

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.