ClinVar Genomic variation as it relates to human health

The c.1061-1G>C variant in the LDLR gene disrupts the canonical splice acceptor site in intron 7 and is predicted to result in abnormal mRNA splicing. This variant has been reported in an individual with familial hypercholesterolemia (PMID: 10487495 ). It is absent from population databases such as gnomAD. Functional studies of this variant show a decrease in LDLR mRNA, skipping of exon 8 and alternative RNA editing using a cryptic acceptor splice site producing a frameshift mutation and a predicted premature stop codon (PMID: 10487495). In addition, another nucleotide change at the same position, c.1061-1G>A, has also been reported in individuals with familial hypercholesterolemia (PMID:17539906). The c.1061-1G>C variant in the LDLR gene is thus classified as likely pathogenic.

This variant is located in a canonical splice-acceptor site and interferes with normal LDLR mRNA splicing. The variant has been reported in individuals with familial hypercholesterolemia in the published literature (PMID: 29407885 (2018) and 10487495 (1999)). In addition, a published study demonstrates that this variant aberrantly affects normal mRNA splicing (PMID: 10487495 (1999)). Based on the available information, this variant is classified as pathogenic.

Variant summary: LDLR c.1061-1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Yu_1999). The variant was absent in 251190 control chromosomes. c.1061-1G>C has been reported in the literature in individuals affected with Familial Hypercholesterolemia (Lind_2002, Yu_1999). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 12052488, 10487495, 18355452). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change affects an acceptor splice site in intron 7 of the LDLR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with familial hypercholesterolemia (PMID: 10487495, 17539906, 28965616; Invitae). ClinVar contains an entry for this variant (Variation ID: 251637). Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 10487495). For these reasons, this variant has been classified as Pathogenic.

The c.1061-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 8 of the LDLR gene. This alteration has been reported in an individual with familial hypercholesterolemia. In addition, RNA and protein studies have revealed aberrant splicing that resulted in abolished expression of wild type LDLR protein (Yu L et al. Atherosclerosis. 1999;146:125-31). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a pathogenic mutation.

Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Deletions involving coding exons of this gene are a known mechanism of disease (HGMD); Different variants affecting the same splice site (c.1061-1 G>A, c.1061-1 G>T) have been reported in association with FH (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); Also known as FH Honduras-1; This variant is associated with the following publications: (PMID: 10487495, 28965616, 29407885, 32906018, 34037665, 33955087, 17539906)