ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1586+5G>C (rs781362878)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000508837 SCV000627020 likely pathogenic Familial hypercholesterolemia 1 2017-05-30 criteria provided, single submitter clinical testing This sequence change falls in intron 10 of the LDLR gene. It does not directly change the encoded amino acid sequence of the LDLR protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with hypercholesterolemia (PMID: 17964958, Invitae). This sequence change has been reported in an individual in the Universal Mutation Database (PMID: 12124988). Nucleotide substitutions within the consensus splice site are relatively common causes 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, but this prediction has not been confirmed by published transcriptional studies. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586202 SCV000697203 likely pathogenic Familial hypercholesterolemia 2016-04-06 criteria provided, single submitter clinical testing Variant summary: c.1586+5G>C affects a conserved nucleotide, resulting in an intronic change. Mutation taster predicts this variant to be disease-causing. 5/5 programs in Alamut predict a loss (or weakening effect) of the canonical splicing donor site and ESE finder predicts changes of binding motifs for RNA splicing enhancers. This variant was not found in 117702 control chromosomes. This variant has been reported in multiple FH pts with evidence of segregation (Yang_JFormosMedAssoc_2008a). Taken together, this variant was classified as Likely Pathogenic until more information becomes available.
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia RCV000508837 SCV001432659 uncertain significance Familial hypercholesterolemia 1 2019-03-10 criteria provided, single submitter research
Mayo Clinic Laboratories, Mayo Clinic RCV001509011 SCV001715492 likely pathogenic not provided 2019-06-01 criteria provided, single submitter clinical testing PM1, PS4_moderate, PP1, PP3
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000508837 SCV000606462 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Broad Institute Rare Disease Group, Broad Institute RCV000586202 SCV001422708 uncertain significance Familial hypercholesterolemia 2020-01-22 no assertion criteria provided curation The c.1586+5G>C variant in LDLR has been reported in at least 2 Taiwanese individuals with familial hypercholesterolemia (PMID: 17964958), and has been identified in 0.02% (4/18384) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs781362878). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported in ClinVar as likely pathogenic and pathogenic (Variation ID#: 440652). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant is located in the 5' splice region. Computational tools do suggest an impact to splicing. However, this information is not predictive enough to determine/rule out pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PS4 (Richards 2015).
Natera, Inc. RCV000586202 SCV001460279 likely pathogenic Familial hypercholesterolemia 2020-09-16 no assertion criteria provided clinical testing

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