ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1503G>A (p.Ala501=) (rs368889457)

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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 RCV000237830 SCV000295473 likely benign Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000237830 SCV000583840 likely pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Color RCV001188900 SCV001356075 uncertain significance Familial hypercholesterolemia 2019-11-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193180 SCV001361868 uncertain significance not specified 2019-02-06 criteria provided, single submitter clinical testing Variant summary: LDLR c.1503G>A alters a non-conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: five predict the variant creates a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.1e-05 in 277202 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (5.1e-05 vs 0.0013), allowing no conclusion about variant significance. c.1503G>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia (Chmara 2010, Martin-Campos 2018). 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as VUS.
Invitae RCV001188900 SCV001417719 uncertain significance Familial hypercholesterolemia 2019-08-16 criteria provided, single submitter clinical testing This sequence change affects codon 501 of the LDLR mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the LDLR protein. This variant is present in population databases (rs368889457, ExAC 0.02%). This variant has been reported in individuals with definite or suspected hypercholesterolemia (PMID: 20145306, 22881376). ClinVar contains an entry for this variant (Variation ID: 251876). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Broad Institute Rare Disease Group,Broad Institute RCV000237830 SCV001423092 uncertain significance Familial hypercholesterolemia 1 2020-01-22 no assertion criteria provided curation The c.1503G>A variant in LDLR has been reported in 4 individuals, including one Polish individual, with Familial Hypercholesterolemia (PMID: 20145306, Variation ID: 251876), and has been identified in 0.02403% (6/24970) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs368889457). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. 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 likely benign and likely pathogenic in ClinVar (Variation ID: 251876). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Multiple missense variants in the same region as c.1503G>A have been reported in association with disease in ClinVar, suggesting that this variant is in a mutational hot spot and slightly supports pathogenicity (Variation ID: 251867, 251868, 251870, 265903, 251874, 251873, 251877). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP3, PS4_Supporting, PM1_Supporting (Richards 2015).

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