Submissions for variant NM_000527.5(LDLR):c.681C>G (p.Asp227Glu)

dbSNP: rs121908028

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000003876	SCV000294902	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000003876	SCV000484734	likely pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	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
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000003876	SCV000583721	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000003876	SCV000599342	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	curation
Laboratory for Molecular Medicine, Mass General Brigham Personalized 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.
Iberoamerican FH Network	RCV000003876	SCV000748135	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV000771320	SCV000903585	pathogenic	Familial hypercholesterolemia	2023-01-23	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, 34037665, 34297352). This variant has also been observed in compound heterozygous state in an individual affected with homozygous familial hypercholesterolemia (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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000771320	SCV000940292	pathogenic	Familial hypercholesterolemia	2025-01-14	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 363,995 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000003876	SCV001432571	pathogenic	Hypercholesterolemia, familial, 1	2019-06-05	criteria provided, single submitter	research
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	RCV000003876	SCV001653604	pathogenic	Hypercholesterolemia, familial, 1	2021-05-24	criteria provided, single submitter	clinical testing
GeneDx	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)
Mayo Clinic Laboratories, Mayo Clinic	RCV001823092	SCV002103274	pathogenic	not provided	2021-07-21	criteria provided, single submitter	clinical testing	PS1, PS3, PS4, PM1, PM2, PM3, PM5, PP3
AiLife Diagnostics, AiLife Diagnostics	RCV001823092	SCV002501901	pathogenic	not provided	2022-01-26	criteria provided, single submitter	clinical testing
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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	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
Revvity Omics, Revvity	RCV000003876	SCV003827695	pathogenic	Hypercholesterolemia, familial, 1	2022-03-21	criteria provided, single submitter	clinical testing
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV000771320	SCV004123055	pathogenic	Familial hypercholesterolemia	2023-07-01	criteria provided, single submitter	research
Genetics and Molecular Pathology, SA Pathology	RCV000003876	SCV004175303	pathogenic	Hypercholesterolemia, familial, 1	2020-11-27	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000003876	SCV004807552	pathogenic	Hypercholesterolemia, familial, 1	2024-03-29	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	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.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	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.
OMIM	RCV000003876	SCV000024041	pathogenic	Hypercholesterolemia, familial, 1	2001-01-01	no assertion criteria provided	literature only
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000003876	SCV000268580	pathogenic	Hypercholesterolemia, familial, 1	2008-06-25	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000003876	SCV000606198	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000003876	SCV001190761	likely pathogenic	Hypercholesterolemia, familial, 1	2020-02-05	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000771320	SCV002086381	pathogenic	Familial hypercholesterolemia	2020-12-02	no assertion criteria provided	clinical testing