Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
LDLR- |
RCV000238115 | SCV000295983 | pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Labcorp Genetics |
RCV001828123 | SCV000544639 | pathogenic | Familial hypercholesterolemia | 2023-06-04 | criteria provided, single submitter | clinical testing | This variant is present in population databases (rs767790696, gnomAD 0.0009%). This sequence change affects an acceptor splice site in intron 16 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). Disruption of this splice site has been observed in individuals with familial hypercholesterolemia (PMID: 8141835, 10441197, 12052488, 16465405, 20145306, 21382890, 22698793). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site is associated with altered splicing resulting in unknown protein product impact (PMID: 8141835). ClinVar contains an entry for this variant (Variation ID: 252313). |
Fundacion Hipercolesterolemia Familiar | RCV000238115 | SCV000607701 | pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | research | |
Robarts Research Institute, |
RCV000238115 | SCV000782940 | pathogenic | Hypercholesterolemia, familial, 1 | 2018-01-02 | criteria provided, single submitter | clinical testing | |
Brunham Lab, |
RCV000238115 | SCV001432636 | pathogenic | Hypercholesterolemia, familial, 1 | 2019-06-05 | criteria provided, single submitter | research | |
Ambry Genetics | RCV002450749 | SCV002737105 | pathogenic | Cardiovascular phenotype | 2023-07-26 | criteria provided, single submitter | clinical testing | The c.2390-2A>G intronic variant results from an A to G substitution two nucleotides before coding exon 17 of the LDLR gene. 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. Based on data from gnomAD, the G allele has an overall frequency of <0.001% (1/251074) total alleles studied. The highest observed frequency was 0.001% (1/113722) of European (non-Finnish) alleles. This alteration has been reported in multiple familial hypercholesterolemia (FH) cohorts and functional studies have shown this alteration to have an impact on splicing (Lombardi, 1993; Peeters, 1999; Lind, 2002; Alonso, 2009; Chmara, 2010; van der Graaf, 2011; Huijgen, 2012). This nucleotide position is highly conserved in available vertebrate species. 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. Based on the available evidence, this alteration is classified as pathogenic. |
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000238115 | SCV000606639 | pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research | ||
Natera, |
RCV001828123 | SCV002086877 | pathogenic | Familial hypercholesterolemia | 2021-01-05 | no assertion criteria provided | clinical testing |