ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.2390-2A>G

dbSNP: rs767790696
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000238115 SCV000295983 pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Invitae 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, Western University RCV000238115 SCV000782940 pathogenic Hypercholesterolemia, familial, 1 2018-01-02 criteria provided, single submitter clinical testing
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia 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, Academisch Medisch Centrum RCV000238115 SCV000606639 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research
Natera, Inc. RCV001828123 SCV002086877 pathogenic Familial hypercholesterolemia 2021-01-05 no assertion criteria provided clinical testing

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