Total submissions: 32
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000003876 | SCV005903150 | pathogenic | Hypercholesterolemia, familial, 1 | 2022-04-29 | reviewed by expert panel | curation | NM_000527.5(LDLR):c.681C>G (p.Asp227Glu) variant, also known as ‘FH Afrikaner-1’ or ‘FH Maine’, is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS4, PP1_Strong, PS3_Moderate, PM1, PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 29 April 2022. The supporting evidence is as follows: PM2: PopMax MAF = 0.00002899 (0.003%) in Latino/Admixed American exomes (gnomAD v2.1.1). PP3: REVEL = 0.864. PM1: Variant meets PM2 and is missense located in exon 4. PS3_Moderate: Level 2 assay PMID 1301956 (Hobbs et al., 1992): Homozygous patient's fibroblasts studied with radiolabeled LDL results in 5-15% LDLR activity. Functional study is consistent with damaging effect. Level 2 assay PMID 2569482 (Leitersdorf et al., 1989): Partial cycle of LDLR studied in CHO Cells. WB after immunoprecipitation of radiolabelled LDLR variant show <50% of WT LDLR expression. PS4, PP4: Variant meets PM2 and is identified in 33 index cases who fulfil SB criteria for FH (n=1 CGMC, UFGOD, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière) or DLCN criteria for FH (n=2 Robarts Research Institute; n=2 Color Health, Inc.; n=3 CGMC, UFGOD, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière; n=25 Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA). PP1_Strong: Variant segregates with FH in at least 22 informatives meioses from at least 2 families from different labs (Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA, Australia): 20 affected family members have the variant and 2 unaffected family members do not have the variant. |
| Variantyx, |
RCV000003876 | SCV007595391 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2025-08-20 | 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 identified in the homozygous or compound heterozygous state in at least 15 cases in the literature (PMID: 2569482, 29284604) (PM3). Multiple computational algorithms predict a deleterious effect for this variant (REVEL score: 0.864) (PP3)., which has a 0.0017% 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. |
| Ce |
RCV001823092 | SCV006098963 | pathogenic | not provided | 2025-05-01 | criteria provided, single submitter | clinical testing | LDLR: PS1, PM1, PM2, PM5, PS4:Moderate, PS3:Supporting |
| Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, |
RCV005403714 | SCV006067659 | pathogenic | Dyslipidemia | 2024-11-22 | criteria provided, single submitter | clinical testing | PS3, PS4, PP1_strong, PM1, PM2, PM3, PP3, PP4 |
| Human Genome Sequencing Center Clinical Lab, |
RCV000771320 | SCV005045761 | pathogenic | Familial hypercholesterolemia | 2019-01-30 | criteria provided, single submitter | clinical testing | The c.681C>G (p.Asp227Glu) variant, also known as p.Asp206Glu, FH-Afrikaner-1, FH Maine, FH-1a and 4D in LDLR gene that encodes for low density lipoprotein receptor, has been identified in numerous individuals (>50) affected with familial hypercholesterolemia (FH) (PMID:8093663, 21310417, 27765764, 26892515, 23375686, 11810272, 17087781, 15199436, 9664576, 7718024, 1952806, 2569482, 8399083). This variant is a founder allele in the Afrikaner population and has been shown to segregate with disease in many families (PMID: 2352257, 11491306, 8399083). This variant lies in the well-established LDL binding domain (amino acids 105-232) critical for protein function (PMID: 2600087). In-silico computational prediction tools suggest that the p.Asp227Glu variant may have deleterious effect on the protein function (REVEL score: 0.864). This variant is found to be rare (2/248142; 0.00000806) in the general population database, gnomAD and interpreted as likely pathogenic/pathogenic by several submitters in the ClinVar database (ClinVar ID: 3690). Therefore, the c.681C>G (p.Asp227Glu) variant in LDLR gene is classified as pathogenic. |
| All of Us Research Program, |
RCV000003876 | SCV004820196 | pathogenic | Hypercholesterolemia, familial, 1 | 2024-01-10 | criteria provided, single submitter | clinical testing | This variant (also known as p.Asp206Glu in the mature protein and as FH-Afrikaner-1, FH Maine, FH-1a, and 4D) is a missense variant located in the fifth LDLR type A repeat in the ligand binding domain of the LDLR protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). Experimental functional studies have indicated that the variant may impair LDLR activity (PMID: 6324732, 3202825, 2569482, 1301956, 1463746). This variant is a founder allele in the Afrikaner population and has been shown to segregate with disease in many families (PMID: 2569482, 2352257, 11491306) and has been reported in numerous unrelated individuals affected with familial hypercholesterolemia from multiple ethnicities (PMID: 2569482, 2352257 1952806, 8093663, 7718024, 9664576, 11491306, 15199436, 17087781, 11810272, 21310417, 23375686, 26892515, 27765764, 33955087, 33994402, 34297352). This variant has been identified in 2/244544 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic. |
| Genomic Medicine Center of Excellence, |
RCV000003876 | SCV004807552 | pathogenic | Hypercholesterolemia, familial, 1 | 2024-03-29 | criteria provided, single submitter | clinical testing | |
| Genetics and Molecular Pathology, |
RCV000003876 | SCV004175303 | pathogenic | Hypercholesterolemia, familial, 1 | 2020-11-27 | criteria provided, single submitter | clinical testing | |
| Division of Human Genetics, |
RCV000771320 | SCV004123055 | pathogenic | Familial hypercholesterolemia | 2023-07-01 | criteria provided, single submitter | research | |
| Revvity Omics, |
RCV000003876 | SCV003827695 | pathogenic | Hypercholesterolemia, familial, 1 | 2024-09-26 | criteria provided, single submitter | clinical testing | |
| Victorian Clinical Genetics Services, |
RCV000003876 | SCV002768391 | pathogenic | Hypercholesterolemia, familial, 1 | 2020-05-21 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to glutamic acid (exon 4). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (Ldl_recept_a domain and is a calcium binding site; NCBI). (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals (ClinVar). (P) 1102 - Strong phenotype match. (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign |
| Ambry Genetics | RCV002362555 | SCV002664715 | pathogenic | Cardiovascular phenotype | 2024-06-07 | criteria provided, single submitter | clinical testing | The p.D227E pathogenic mutation (also known as c.681C>G), located in coding exon 4 of the LDLR gene, results from a C to G substitution at nucleotide position 681. The aspartic acid at codon 227 is replaced by glutamic acid, an amino acid with highly similar properties. This founder mutation (also referred to as p.D206I accounts for the majority of familial hypercholesterolemia (FH) in the Afrikaner population (Leitersdorf et al. J Clin Invest.1989;84(3):954-61; King et al. N Z Med J. 2010;123(1319):79-82). This alteration has been reported in affected individuals of multiple ethnicities in both the heterozygous and homozygous states (e.g., Gudnason et al. Arterioscler. Thromb. 1993;13(1):56-63; Leren et al. Semin Vasc Med. 2004;4(1):75-85; Bertolini et al Atherosclerosis 2013;227(2):342-348; Sharifi et al. Metab. Clin. Exp. 2016;65(3):48-53). In an assay testing LDLR function, this variant showed a functionally abnormal result (Fourie A et al. Biochem J. 1988;255(2):411-5). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Ai |
RCV001823092 | SCV002501901 | pathogenic | not provided | 2022-01-26 | criteria provided, single submitter | clinical testing | |
| Mayo Clinic Laboratories, |
RCV001823092 | SCV002103274 | pathogenic | not provided | 2021-07-21 | criteria provided, single submitter | clinical testing | PS1, PS3, PS4, PM1, PM2, PM3, PM5, PP3 |
| Natera, |
RCV000771320 | SCV002086381 | pathogenic | Familial hypercholesterolemia | 2025-08-11 | criteria provided, single submitter | clinical testing | The c.681C>G variant in LDLR is a missense variant predicted to cause substitution of aspartic acid to glutamic acid at amino acid 227. 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: 10669652, 30270076, 32911577, 36229885). Additionally, this variant has been observed to segregate in affected family members (PMID: 10669652, 30270076). Computational prediction algorithms indicate this variant is likely to affect gene or protein function. Given the available evidence, this variant is classified as Pathogenic. |
| Gene |
RCV001823092 | SCV002072680 | pathogenic | not provided | 2022-01-17 | criteria provided, single submitter | clinical testing | Disrupts a negatively charged triplet, Ser-Asp-Glu, located at the carboxyl-terminal end of the LDL- receptor class A5 repeat domain that is critical for ligand binding (Schneider et al., 2003); Functional studies demonstrate a damaging effect: creation of two LDLR isoforms, both with a slower maturation process, and one with inability to bind to the lipoprotein ligand resulting in a reduced rate of lipoprotein degradation (Leitersdorf et al., 1989; Fourie et al., 1992); Common founder variant in the Afrikaner population (Kotze et al., 1993); Not observed at significant frequency in large population cohorts (gnomAD); 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: 3202825, 2352257, 23375686, 2569482, 11810272, 26892515, 8093663, 9664576, 17087781, 2565980, 1463746, 30270076, 31048103, 29284604, 31447099, 32977124, 32041611, 32922439, 33740630, 34037665, 33087929, 28965616, 30592178, 27680772, 12827279, 3430554, 8399083) |
| Laboratory of molecular diagnosis of dyslipidemias, |
RCV000003876 | SCV001653604 | pathogenic | Hypercholesterolemia, familial, 1 | 2021-05-24 | criteria provided, single submitter | clinical testing | |
| Brunham Lab, |
RCV000003876 | SCV001432571 | pathogenic | Hypercholesterolemia, familial, 1 | 2019-06-05 | criteria provided, single submitter | research | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000771320 | SCV001361870 | pathogenic | Familial hypercholesterolemia | 2023-07-24 | criteria provided, single submitter | clinical testing | Variant summary: LDLR c.681C>G (p.Asp227Glu) results in a conservative amino acid change located in the fifth class A repeat domain (IPR002172) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 248142 control chromosomes (gnomAD). c.681C>G has been reported in the literature in the heterozygous, homozygous, or compound heterozygous state in numerous individuals affected with Familial Hypercholesterolemia (e.g. Kotze_1990, Gudnason_1994, Bertolini_2013, Sharifi_2016, Thedrez_2018). The variant has also been described as a founder variant within the Afrikaner population and it has been estimated that approximately 65% of affected South African Afrikaners carry this variant (Kotze_1990). These data indicate that the variant is very likely to be associated with disease. Publications reporting experimental evidence evaluating an impact on protein function found slower processing and decreased cell surface expression for the variant protein (e.g. Leitersdorf_1989, Thedrez_2018). The following publications have been ascertained in the context of this evaluation (PMID: 23375686, 7947594, 2352257, 2569482, 26892515, 29284604). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=16)/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. |
| Labcorp Genetics |
RCV000771320 | SCV000940292 | pathogenic | Familial hypercholesterolemia | 2025-12-22 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 227 of the LDLR protein (p.Asp227Glu). This variant is present in population databases (rs121908028, gnomAD 0.003%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 2352257, 2569482, 17539906, 19467224, 21310417, 21382890, 22883975, 23375686, 23669246, 27680772). It is commonly reported in individuals of Afrikaner ancestry (PMID: 2352257, 2569482). 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 Asp206Glu and FH Afrikaner-1. ClinVar contains an entry for this variant (Variation ID: 3690). 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%. Experimental studies have shown that this missense change affects LDLR function (PMID: 2569482). For these reasons, this variant has been classified as Pathogenic. |
| Color Diagnostics, |
RCV000771320 | SCV000903585 | pathogenic | Familial hypercholesterolemia | 2024-03-05 | criteria provided, single submitter | clinical testing | This missense variant replaces aspartic acid with glutamic acid at codon 227 of the LDLR protein. This variant is also known as p.Asp206Glu in the mature protein, as well as and as FH-Afrikaner-1, FH Maine, FH-1a, FH Reggio Emilia-2, and 4D in the literature. This variant alters a conserved aspartic acid residue in the LDLR type A repeat 5 of the LDLR protein (a.a. 195-232), 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. Experimental functional studies have indicated that the variant may impair LDLR activity (PMID: 1301956, 1463746, 2569482, 6324732, 3202825). This variant is a founder allele in the Afrikaner population and has been shown to segregate with disease in many families (PMID: 2569482, 2352257, 11491306) and has been reported in numerous unrelated individuals affected with familial hypercholesterolemia from multiple ethnicities (PMID: 1952806, 2352257, 2565980, 2569482, 3430554, 7718024, 8093663, 9664576, 11491306, 11810272, 15199436, 17087781, 21310417, 23375686, 26892515, 27765764, 33955087, 33994402, 34297352, 34037665, 35194765, 37119068, 37225774). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 11491306, 2352257, 2569482).This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in one individual affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 36229885). This variant has been identified in 2/248142 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic. |
| Iberoamerican FH Network | RCV000003876 | SCV000748135 | pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | research | |
| Laboratory for Molecular Medicine, |
RCV000003876 | SCV000731597 | pathogenic | Hypercholesterolemia, familial, 1 | 2022-06-29 | criteria provided, single submitter | clinical testing | The p.Asp227Glu variant in LDLR has been reported in >20 heterozygous individuals with familial hypercholesterolemia and segregated in at least 10 affected family members (Gudnason 1993 PMID: 8093663, Callis 1998 PMID: 9664576, Chan 2019 PMID: 30592178, Fouchier 2001 PMID: 11810272, Sharifi 2016 PMID: 26892515, Trinder 2019 PMID: 31345425, van der Graaf 2011 PMID: 21382890). It has been reported as the FH Afrikaner 1 allele, a founder variant in the white Afrikaner-speaking population of South Africa, and is thought to account for 65 - 75% of familial hypercholesterolemia in this population (Leitersdorf 1989 PMID: 2569482, Kotze 1990 PMID: 2352257 , Kotze 1994 PMID: 8399083). It has been reported in ClinVar (Variation ID 3690) and in several patients with homozygous FH (Leitersdorf 1989 PMID: 2569482, Bertolini 2013 PMID: 23375686, Pirillo 2017 PMID: 28965616, Truong 2018 PMID: 30270076, Luirink 2019 PMID: 31048103). The c.681C>G, p.(Asp227Glu) variant has also been reported with legacy nomenclature as D206E. Additionally, in vitro functional studies provide some evidence that the p.Asp227Glu variant may impair receptor activity (Fourie 1988 PMID: 3202825). This variant has been identified in 1/34492 of Latino/Admixed American and in 1/112078 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of FH in the general population. In summary, this variant meets criteria to be classified as pathogenic for FH. ACMG/AMP criteria applied: PS4, PP1_Strong, PM2_Supporting, PP3, PS3_Supporting. |
| Cardiovascular Research Group, |
RCV000003876 | SCV000599342 | pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | curation | |
| U4M - |
RCV000003876 | SCV000583721 | pathogenic | Hypercholesterolemia, familial, 1 | 2017-03-30 | criteria provided, single submitter | clinical testing | |
| Centre de Génétique Moléculaire et Chromosomique, |
RCV000003876 | SCV000503215 | pathogenic | Hypercholesterolemia, familial, 1 | 2016-12-16 | criteria provided, single submitter | clinical testing | subjects mutated among 2600 FH index cases screened = 6 , family members = 3 with co-segregation / FH-Afrikaner-1 / Software predictions: Damaging |
| Robarts Research Institute, |
RCV000003876 | SCV000484734 | likely pathogenic | Hypercholesterolemia, familial, 1 | criteria provided, single submitter | clinical testing | ||
| LDLR- |
RCV000003876 | SCV000294902 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| Biochemical Molecular Genetic Laboratory, |
RCV000003876 | SCV001190761 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2020-02-05 | no assertion criteria provided | clinical testing | |
| Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000003876 | SCV000606198 | pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research | ||
| Cardiovascular Genetics Laboratory, |
RCV000003876 | SCV000268580 | pathogenic | Hypercholesterolemia, familial, 1 | 2008-06-25 | no assertion criteria provided | clinical testing | |
| OMIM | RCV000003876 | SCV000024041 | pathogenic | Hypercholesterolemia, familial, 1 | 2001-01-01 | no assertion criteria provided | literature only |