ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.940+16G>A

gnomAD frequency: 0.00028  dbSNP: rs72658859
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000238259 SCV000295081 likely benign Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Invitae RCV002055015 SCV002361757 likely benign Familial hypercholesterolemia 2024-01-25 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002298555 SCV002598648 uncertain significance not specified 2023-07-17 criteria provided, single submitter clinical testing Variant summary: LDLR c.940+16G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00014 in 250436 control chromosomes (gnomAD v2.1, Exomes dataset). This frequency is not significantly higher than expected for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (0.00014 vs 0.0013), allowing no conclusion about variant significance. c.940+16G>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia (e.g., Chmara_2010, Noto_2022). These reports do 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 publications have been ascertained in the context of this evaluation (PMID: 20145306, 35339733). Three ClinVar submitters (evaluation after 2014) have cited the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics RCV003298313 SCV004000124 likely benign Cardiovascular phenotype 2023-04-12 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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