ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1846-1G>A (rs879255051)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000238026 SCV000295711 pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000238026 SCV000322982 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research 0/220 non-FH alleles
Robarts Research Institute,Western University RCV000238026 SCV000484788 likely pathogenic Familial hypercholesterolemia 1 criteria provided, single submitter clinical testing
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000238026 SCV000540844 pathogenic Familial hypercholesterolemia 1 2016-11-05 criteria provided, single submitter clinical testing
Invitae RCV000791432 SCV000544663 pathogenic Familial hypercholesterolemia 2019-11-18 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 12 of the LDLR gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant has been reported in the literature in individuals affected with a hypercholesterolemia (PMID: 8828981, 11317362, 11737238, 15359125, 16542394, 20828696). In summary, donor and acceptor splice site variants are typically loss-of-function (PMID: 16199547), and loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525). For these reasons, this variant has been classified as Pathogenic.
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000238026 SCV000583893 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000791432 SCV001338276 pathogenic Familial hypercholesterolemia 2020-02-03 criteria provided, single submitter clinical testing Variant summary: LDLR c.1846-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: 4/4 tools predict that the variant abolishes or weakens a 3' acceptor site. Several publications report experimental evidence that this variant affects mRNA splicing (examples-Hobbs_1992, Bertolini_1999). The variant allele was found at a frequency of 3.2e-05 in 31408 control chromosomes (gnomAD genomes). c.1846-1G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (examples- Hobbs_1992, Jensen_1996, Bertolini_1999, Kim_2004, Madeiros_2014). These data indicate that the variant is very likely to be associated with disease. The variant has also been referred to in the literature as "FH-Tunis" and FH-Avellino-2". Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal LDL-receptor activity (Hobbs_1992). Five ClinVar submitters (evaluation after 2014) have cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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