ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.2547+1G>A

dbSNP: rs879255224
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237756 SCV000296031 pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge RCV000237756 SCV000323015 pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research 0/188 non-FH alleles
Invitae RCV001043694 SCV001207452 pathogenic Familial hypercholesterolemia 2022-02-05 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 17 of the LDLR gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. 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: 17765246; Invitae). ClinVar contains an entry for this variant (Variation ID: 252352). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in skipping of exon 17 and introduces a new termination codon (PMID: 20828696). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV001043694 SCV001434859 pathogenic Familial hypercholesterolemia 2019-02-01 criteria provided, single submitter clinical testing The c.2547+1G>A variant in the LDLR gene disrupts the canonical splice donor site in intron 17 and is predicted to result in abnormal splicing of LDLR mRNA. This variant is absent from general population databases and has been reported in two unrelated individuals with hypercholesterolemia (PMID 17765246). In addition, skipping of exon 17 and a premature codon at aa805 were observed using mRNA extracted from the blood sample of an individual carrying this variant (PMID 20828696). Thus, this c.2547+1G>A variant in the LDLR gene is classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV003480571 SCV004227685 likely pathogenic not provided 2022-08-17 criteria provided, single submitter clinical testing PM2, PS4_supporting, PVS1_strong
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000237756 SCV000606667 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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