ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.314-1G>A

dbSNP: rs879254471
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237693 SCV000294622 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge RCV000237693 SCV000599326 pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter curation
Invitae RCV001824705 SCV000824886 pathogenic Familial hypercholesterolemia 2023-01-20 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys109 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9544745, 11313767, 22883975, 24956927). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Studies have shown that disruption of this splice site results in skipping of exon 4, but is expected to preserve the integrity of the reading-frame (PMID: 19208450). ClinVar contains an entry for this variant (Variation ID: 251148). This variant is also known as S285L. Disruption of this splice site has been observed in individuals with familial hypercholesterolemia (PMID: 9452078, 31048103). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 3 of the LDLR gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute RCV001256969 SCV001433512 pathogenic not provided 2019-06-17 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001824705 SCV002074178 pathogenic Familial hypercholesterolemia 2022-01-10 criteria provided, single submitter clinical testing Variant summary: LDLR c.314-1G>A alters a conserved nucleotide 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: Four predict the variant abolishes the canonical 3' splice acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing resulting in skipping of exon 4 (example, Holla_2009). The variant was absent in 249626 control chromosomes. c.314-1G>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia (example, Lombardi_1998, Luirink_2019, Fouchier_2001). At least one publication reports experimental evidence evaluating an impact on protein function (example, Holla_2009). The most pronounced variant effect results in decrease in LDL-receptor activity (approximately 41% of wild type), decrease in LDL internalization (approximately 30% of wild type) and decrease in cell surface LDL-receptor levels (approximately 50% of wild type). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics RCV002321914 SCV002610619 pathogenic Cardiovascular phenotype 2021-05-24 criteria provided, single submitter clinical testing The c.314-1G>A pathogenic mutation, results from a G to A one nucleotide upstream from coding exon 4 of the LDLR gene. This alteration has been reported in familial hypercholestremia (FH) patients (Huijgen et al 2010; Hum Mut 31(6):752-60; Lombardi P et al. Hum Mutat, 1998;Suppl 1:S172-4; Luirink IK et al. Atherosclerosis, 2019 06;285:87-92). This alteration has also been shown to have an impact on protein function (Holla ØL et al. Mol Genet Metab, 2009 Apr;96:245-52). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Revvity Omics, Revvity RCV000237693 SCV003827795 pathogenic Hypercholesterolemia, familial, 1 2022-08-31 criteria provided, single submitter clinical testing
GeneDx RCV001256969 SCV003915310 pathogenic not provided 2022-10-04 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant expected to result in aberrant splicing and loss of adjacent in-frame exon; Published functional studies using flow cytometry in patient cells show abnormal splicing leading to skipping of exon 4 or retention of intron 3 (Holla et al., 2009); Deletions involving coding exons of this gene are a known mechanism of disease (HGMD); This variant is associated with the following publications: (PMID: 22294733, 25911074, 11810272, 20506408, 21382890, 22390909, 30795984, 31048103, 9452078, 19208450)
All of Us Research Program, National Institutes of Health RCV000237693 SCV004841362 pathogenic Hypercholesterolemia, familial, 1 2023-10-23 criteria provided, single submitter clinical testing This variant causes a G to A nucleotide substitution at the -1 position of intron 3 of the LDLR gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. A functional RNA study using lymphocytes derived from a heterozygous carrier individual has shown that this variant causes abnormal splicing, leading to skipping of exon 4 (PMID: 19208450). Additionally, flow cytometry analysis of these carrier-derived lymphocytes has shown that this variant causes a significant reduction in residual LDLR activity (PMID: 19208450). This variant has been reported in more than 10 individuals affected with familial hypercholesterolemia (PMID: 9452078, 11810272, 20506408, 21382890, 30795984, 31048103, 36604244). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease ( Based on the available evidence, this variant is classified as Pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000237693 SCV000606081 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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