ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.2547+5G>A

dbSNP: rs879255226
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001321571 SCV001512407 uncertain significance Familial hypercholesterolemia 2023-09-03 criteria provided, single submitter clinical testing This sequence change falls in intron 17 of the LDLR gene. It does not directly change the encoded amino acid sequence of the LDLR protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 27816806; Invitae). ClinVar contains an entry for this variant (Variation ID: 440702). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV002264950 SCV002546741 likely pathogenic not provided 2022-06-30 criteria provided, single submitter clinical testing Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and splice predictors support a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27816806)
Ambry Genetics RCV002431470 SCV002740622 uncertain significance Cardiovascular phenotype 2021-02-02 criteria provided, single submitter clinical testing The c.2547+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 17 in the LDLR gene. This variant was detected in a child with homozygous familial hypercholesterolemia, including significantly elevated cholesterol levels, xanthomas, and corneal arcus; her parents were reportedly consanguineous with elevated LDL cholesterol levels (Setia N et al. Atherosclerosis, 2016 12;255:31-36). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003323578 SCV004028786 uncertain significance not specified 2023-07-05 criteria provided, single submitter clinical testing Variant summary: LDLR c.2547+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens the canonical 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251266 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2547+5G>A has been reported in the literature in a three year old individual affected with familial hypercholesterolemia and her parents were reportedly consanguineous with elevated LDL cholesterol levels (example: Setia_2016). This report does not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 27816806). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000508841 SCV000606668 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.