Total submissions: 32
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000237148 | SCV002568114 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2022-01-19 | reviewed by expert panel | curation | NM_000527.5(LDLR):c.858C>A (p.Ser286Arg) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PS4_Supporting, PP1, PP3 and PP4) 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 - PopMax MAF = 0.00006155 (0.006155%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1). PS4_Supporting - Variant meets PM2 and is identified in 4 unrelated index cases who fulfil DLCN >=6 (1 case in PMID: 32770674; 2 cases from Robarts Research Institute) or SB definitive ( 1 case from Molecular Genetics Laboratory of Centre for Cardiovascular Surgery and Transplantation). PP1 - Variant segregates with FH phenotype in 2 informative meiosis from 2 unrelated families (1 case from Molecular Genetics Laboratory of Centre for Cardiovascular Surgery and Transplantation and 1 case from Robarts Research Institute). PP3 - REVEL = 0.766. PP4 - Variant meets PM2 and is identified in 4 index cases who fulfil DLCN >=6 (1 case in PMID: 32770674; 2 cases from Robarts Research Institute) or SB definitive ( 1 case from Molecular Genetics Laboratory of Centre for Cardiovascular Surgery and Transplantation). |
| Genetics Laboratory, |
RCV000590088 | SCV007596544 | likely pathogenic | Familial hypercholesterolemia | 2026-03-26 | criteria provided, single submitter | clinical testing | PS4_strong, PM2_moderate, PP3_supporting |
| Variantyx, |
RCV000237148 | SCV007595395 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2025-11-11 | criteria provided, single submitter | clinical testing | This is a nonsynonymous variant in the LDLR gene (OMIM: 606945). Pathogenic variants in this gene have been associated with autosomal semidominant familial hypercholesterolemia 1. This variant has been reported in several unrelated affected individuals (PMID: 11462246, 17347910, 23130880, 11810272, 27578104, 27765764) (PS4). Functional studies have shown that this variant alters LDLR protein function (PMID: 1301956) (PS3_Moderate), and multiple computational algorithms predict a deleterious effect for this variant (REVEL score: 0.766) (PP3). This variant has a 0.0016% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/) (PM2). Based on the current evidence, this variant is classified as likely pathogenic for autosomal semidominant familial hypercholesterolemia 1. |
| Natera, |
RCV000590088 | SCV007527849 | likely pathogenic | Familial hypercholesterolemia | 2025-05-12 | criteria provided, single submitter | clinical testing | The c.858C>A variant in LDLR is a missense variant predicted to cause substitution of serine to arginine at amino acid 286. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 1301956, 37850379, 34496902). Computational prediction algorithms indicate this variant is likely to affect gene or protein function. Given the available evidence, this variant is classified as Likely Pathogenic. |
| Institute of Human Genetics Munich, |
RCV000237148 | SCV006302596 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2024-01-22 | criteria provided, single submitter | clinical testing | |
| 3billion | RCV000237148 | SCV005904233 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2023-06-08 | criteria provided, single submitter | clinical testing | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.77; 3Cnet: 0.94). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000251488 /PMID: 1301956). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. |
| Victorian Clinical Genetics Services, |
RCV000237148 | SCV005400336 | pathogenic | Hypercholesterolemia, familial, 1 | 2025-07-22 | criteria provided, single submitter | clinical testing | This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD (v2) <0.01 (7 heterozygotes, 0 homozygotes); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as likely pathogenic or pathogenic (ClinVar); Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. Additional information: Variant is predicted to result in a missense amino acid change from serine to arginine; This variant is heterozygous; This gene is associated with both recessive and dominant disease. Variants have been reported in heterozygous, compound heterozygous and homozygous states with the recessive disease being more severe (OMIM, PMID: 10978268); Variant is located in the annotated Ldl_recept_a domain (DECIPHER); Loss of function is a known mechanism of disease in this gene and is associated with familial hypercholesterolaemia 1 (FH; MIM#143890); The condition associated with this gene has incomplete penetrance (PMID: 24404629); This variant has been shown to be paternally inherited by trio analysis. |
| Clinical Genetics Laboratory, |
RCV000590088 | SCV005198650 | likely pathogenic | Familial hypercholesterolemia | 2025-01-23 | criteria provided, single submitter | clinical testing | |
| Laboratory for Molecular Medicine, |
RCV000237148 | SCV004847825 | pathogenic | Hypercholesterolemia, familial, 1 | 2021-05-28 | criteria provided, single submitter | clinical testing | The p.Ser286Arg variant in LDLR has been reported in more than 25 individuals with hypercholesterolemia and segregated with disease in at least 27 affected individuals from multiple families (Hobbs 1992 PMID: 1301956, Bertolini 2013 PMID: 23375686, Mollaki 2014 PMID: 27578104). Notably, the variant appears to be associated with a milder hypercholesterolemia phenotype (Huijgen 2012 PMID: 22390909). This variant has also been reported in by other clinical laboratories in ClinVar (Variation ID 251488) and has been identified in 0.006% (7/113726) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of familial hypercholesterolemia (FH) in the general population. In vitro functional studies support an impact on protein function (Hobbs 1992 PMID: 1301956) and computational prediction tools and conservation analyses are consistent with pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2_supporting, PS3_Supporting, PP3. |
| All of Us Research Program, |
RCV000237148 | SCV004820223 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2023-12-14 | criteria provided, single submitter | clinical testing | This missense variant (also known as p.Ser265Arg in the mature protein and as FH Greece-2) replaces serine with arginine at codon 286 in the LDLR type A repeat 7 of the ligand binding domain of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An experimental functional study has shown that this variant in compound heterozygosity with p.Cys173Arg reduces LDLR activity to 5-15% compared to wild type (PMID: 1301956). This variant has been reported in numerous individuals affected with familial hypercholesterolemia (PMID: 11462246, 11810272, 15015036, 17347910, 23130880, 27578104, 27765764, 28965616, 32829317, 33454241, 33794673; Color Health internal data) and is a recurrent mutation in the Greek population (PMID: 27578104). This variant has been identified in 7/251430 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. |
| Institute for Clinical Genetics, |
RCV000985771 | SCV004026104 | likely pathogenic | not provided | 2022-07-25 | criteria provided, single submitter | clinical testing | PS4, PP3, PM2_SUP |
| Revvity Omics, |
RCV000237148 | SCV003829631 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2024-12-06 | criteria provided, single submitter | clinical testing | |
| Ce |
RCV000985771 | SCV002822508 | likely pathogenic | not provided | 2025-09-01 | criteria provided, single submitter | clinical testing | LDLR: PM1, PM2, PP4:Moderate, PS4:Moderate |
| Ambry Genetics | RCV002446473 | SCV002681307 | pathogenic | Cardiovascular phenotype | 2026-03-05 | criteria provided, single submitter | clinical testing | The c.858C>A (p.S286R) alteration is located in exon 6 (coding exon 6) of the LDLR gene. This alteration results from a C to A substitution at nucleotide position 858, causing the serine (S) at amino acid position 286 to be replaced by an arginine (R). Based on data from gnomAD, the A allele has an overall frequency of 0.003% (7/251430) total alleles studied. The highest observed frequency was 0.006% (7/113726) of European (non-Finnish) alleles. This variant, also referred to as S265R and FH Greece-2, has been detected in several cohorts and multiple unrelated individuals with hypercholesterolemia from various ethnic backgrounds, and has been reported to result in reduced LDL receptor activity (Hobbs, 1992; Day, 1997; Traeger-Synodinos, 1998; Nauck, 2001; Mihaylov, 2004; Whittall, 2010; Huijgen, 2012; Mollaki, 2014; Klanar, 2015). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. |
| Laboratory of Medical Genetics, |
RCV000237148 | SCV002577585 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2022-05-05 | criteria provided, single submitter | clinical testing | PM1, PM2, PP2, PP3, PP5 |
| Gene |
RCV000985771 | SCV002567378 | pathogenic | not provided | 2022-08-15 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging effect, including a reduction in LDLR activity (Hobbs et al., 1992); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 14974088, 22390909, 15015036, 11462246, 23375686, 27578104, 25463123, 28965616, 34426522, 33303402, 32719484, 32770674, 32977124, 34037665, 1301956) |
| Mayo Clinic Laboratories, |
RCV000985771 | SCV002103275 | pathogenic | not provided | 2022-06-01 | criteria provided, single submitter | clinical testing | PP3, PM2_supporting, PS3_moderate, PS4 |
| Brunham Lab, |
RCV000237148 | SCV001432669 | pathogenic | Hypercholesterolemia, familial, 1 | 2019-05-23 | criteria provided, single submitter | research | |
| Institute of Human Genetics, |
RCV000237148 | SCV001429319 | uncertain significance | Hypercholesterolemia, familial, 1 | 2019-02-14 | criteria provided, single submitter | clinical testing | |
| Color Diagnostics, |
RCV000590088 | SCV001358587 | pathogenic | Familial hypercholesterolemia | 2025-01-06 | criteria provided, single submitter | clinical testing | This missense variant replaces serine with arginine at codon 286 of the LDLR protein. This variant is also known as p.Ser265Arg in the mature protein. This variant alters a conserved serine residue in the LDLR type A repeat 7 of the ligand binding domain of the LDLR protein (a.a. 274-314), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function. An experimental functional study has shown that this variant in compound heterozygosity with p.Cys173Arg reduces LDLR activity to 5-15% compared to wild type (PMID: 1301956). This variant has been reported in over 150 individuals affected with familial hypercholesterolemia (PMID: 11462246, 11810272, 15015036, 17347910, 23130880, 27578104, 27765764, 28965616, 32829317, 33454241, 33794673, 35052492, 35626767; Color Health internal data) and is a recurrent mutation in the Greek population (PMID: 27578104). This variant has been identified in 7/251430 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000985771 | SCV001134271 | pathogenic | not provided | 2024-06-11 | criteria provided, single submitter | clinical testing | The LDLR c.858C>A (p.Ser286Arg) variant has been reported in the published literature in multiple families affected with hypercholesterolemia (PMID: 11462246 (2001), 15015036 (2004), 17347910 (2007), 21925044 (2011), 26361156 (2015), 27765764 (2016), 32770674 (2020), 32977124 (2020), 33794673 (2021), 37409534 (2023)), though it has been reported to produce milder phenotype (PMID: 25463123 (2014)). In a published functional study, this variant resulted in a significant reduction in LDLR activity (PMID: 1301956 (1992)). The frequency of this variant in the general population, 0.000062 (7/113726 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. |
| Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, |
RCV005400718 | SCV000987682 | pathogenic | Dyslipidemia | 2024-07-10 | criteria provided, single submitter | clinical testing | PS4, PP1_strong, PM2, PP3, PP4 |
| Labcorp Genetics |
RCV000590088 | SCV000752422 | pathogenic | Familial hypercholesterolemia | 2025-10-22 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 286 of the LDLR protein (p.Ser286Arg). This variant is present in population databases (rs140241383, gnomAD 0.007%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 1301956, 11317361, 11462246, 15015036, 23130880, 27765764). 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 pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 377,766 individuals referred to our laboratory for LDLR testing. This variant is also known as p.Ser265Arg. ClinVar contains an entry for this variant (Variation ID: 251488). 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%. For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000590088 | SCV000697254 | pathogenic | Familial hypercholesterolemia | 2017-04-06 | criteria provided, single submitter | clinical testing | Variant summary: The LDLR c.858C>A (p.Ser286Arg) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index), which was confirmed by low LDLR activity in patient carrying this variant (Hobbs_1992). This variant was found in 3/121368 control chromosomes at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). This variant has been reported in a large number of FH patients with milder phenotype. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic. |
| U4M - |
RCV000237148 | SCV000583749 | pathogenic | Hypercholesterolemia, familial, 1 | 2017-03-30 | criteria provided, single submitter | clinical testing | |
| Molecular Genetics Laboratory, |
RCV000237148 | SCV000540765 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-11-05 | criteria provided, single submitter | clinical testing | |
| Centre de Génétique Moléculaire et Chromosomique, |
RCV000237148 | SCV000503244 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-12-16 | criteria provided, single submitter | clinical testing | subjects mutated among 2600 FH index cases screened = 6 / FH-Greece-2, 5 to 15% LDLR Activity / Software predictions: Conflicting |
| Robarts Research Institute, |
RCV000237148 | SCV000484736 | likely pathogenic | Hypercholesterolemia, familial, 1 | criteria provided, single submitter | clinical testing | ||
| LDLR- |
RCV000237148 | SCV000295013 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| Diagnostic Laboratory, |
RCV000985771 | SCV001962897 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Clinical Genetics, |
RCV000985771 | SCV001918117 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000237148 | SCV000606249 | pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research |