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

gnomAD frequency: 0.00001  dbSNP: rs375495026

Total submissions: 10

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001176040	SCV003260467	likely pathogenic	Familial hypercholesterolemia	2024-10-23	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 individuals with clinical features of familial hypercholesterolemia (PMID: 23669246, 233740630; internal data). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be benign with a negative predictive value of at least 95%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. ClinVar contains an entry for this variant (Variation ID: 161280). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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; internal data). 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	2024-05-14	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 287 of the LDLR protein. This variant is also known as p.Gly266Ser in the mature protein. This variant alters a conserved glycine residue in the LDLR type A repeat 7of the LDLR protein (a.a. 274-314), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three individuals affected with familial hypercholesterolemia (PMID: 23669246, 33740630, 34182004). This variant has been identified in 3/282818 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Gly287Cys, is considered to be disease-causing (ClinVar variation ID: 251489), suggesting that glycine at this position is important for LDLR protein function. Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
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