ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.859G>A (p.Gly287Ser)

gnomAD frequency: 0.00001  dbSNP: rs375495026
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel RCV000237748 SCV004022420 uncertain significance Hypercholesterolemia, familial, 1 2023-04-28 reviewed by expert panel curation The NM_000527.5 (LDLR):c.859G>A (p.Gly287Ser) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PM5) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: PopMaxMAF=0.00003 in South Asian population in gnomAD (gnomAD v2.1.1). PP3: REVEL=0.902. PM5: One other variant at same codon: NM_000527.5 (LDLR):c.859G>T (p.Gly287Cys), ClinVarID 251489, is classified as Pathogenic by these guidelines, therefore PM5 is met. PS3 not met: Functional data is not available.
LDLR-LOVD, British Heart Foundation RCV000237748 SCV000295014 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Color Diagnostics, LLC DBA Color Health RCV001176040 SCV001339857 uncertain significance Familial hypercholesterolemia 2023-03-01 criteria provided, single submitter clinical testing This missense variant (also known as p.Gly266Ser in the mature protein) replaces glycine with serine at codon 287 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with familial hypercholesterolemia (PMID: 23669246). This variant has been identified in 3/282818 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Genome-Nilou Lab RCV000237748 SCV001653469 likely pathogenic Hypercholesterolemia, familial, 1 2021-05-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002307407 SCV002600399 uncertain significance not specified 2022-10-10 criteria provided, single submitter clinical testing Variant summary: LDLR c.859G>A (p.Gly287Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251434 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.859G>A has been reported in the literature in individuals affected with Hypercholesterolemia without strong evidence for causality (Futema_2013, Trinder_2020, Leren_2021). 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. Another variant located at the same amino acid has been reported in association with Hypercholesterolaemia in HGMD (p.G287C). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics RCV002444606 SCV002679931 uncertain significance Cardiovascular phenotype 2022-10-26 criteria provided, single submitter clinical testing The p.G287S variant (also known as c.859G>A), located in coding exon 6 of the LDLR gene, results from a G to A substitution at nucleotide position 859. The glycine at codon 287 is replaced by serine, an amino acid with similar properties. This alteration has been reported in familial cholesterolemia (FH) cohorts; however, clinical details were limited (Futema M et al. Atherosclerosis, 2013 Jul;229:161-8; Leren TP et al. Atherosclerosis, 2021 04;322:61-66). Additionally, this alteration was reported in a control population of an early onset myocardial infarction cohort (Do R et al. Nature, 2015 Feb;518:102-6). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001176040 SCV003260467 likely pathogenic Familial hypercholesterolemia 2023-10-22 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 287 of the LDLR protein (p.Gly287Ser). This variant is present in population databases (rs375495026, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (PMID: 23669246, 33740630). ClinVar contains an entry for this variant (Variation ID: 161280). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. This variant disrupts the p.Gly287 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12730724, 17196209; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
All of Us Research Program, National Institutes of Health RCV000237748 SCV004820225 uncertain significance Hypercholesterolemia, familial, 1 2023-12-01 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant (also known as p.Gly266Ser in the mature protein) is located in the LDLR type A repeat 7 of the ligand binding domain of the LDLR protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been identified in an individual affected with familial hypercholesterolemia (PMID: 23669246). This variant has also been identified in 3/246246 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively.
CSER _CC_NCGL, University of Washington RCV002051673 SCV000190301 uncertain significance Hypercholesterolemia 2014-06-01 no assertion criteria provided research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000237748 SCV000606251 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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