NM_000527.5(LDLR):c.681C>G (p.Asp227Glu) AND Hypercholesterolemia, familial, 1

Germline classification:: Pathogenic (20 submissions)
Last evaluated:: Apr 29, 2022
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000003876.42

Allele description [Variation Report for NM_000527.5(LDLR):c.681C>G (p.Asp227Glu)]

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

Gene:

LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.2

Genomic location:

Preferred name:

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

Other names:

D206E; FH Afrikaner 1; FH Maine; FH Afrikaner-1; NP_000518.1:p.D227E; NM_000527.5(LDLR):c.681C>G

HGVS:

NC_000019.10:g.11105587C>G
NG_009060.1:g.21207C>G
NM_000527.5:c.681C>GMANE SELECT
NM_001195798.2:c.681C>G
NM_001195799.2:c.558C>G
NM_001195800.2:c.314-1805C>G
NM_001195803.2:c.314-978C>G
NP_000518.1:p.Asp227Glu
NP_000518.1:p.Asp227Glu
NP_001182727.1:p.Asp227Glu
NP_001182728.1:p.Asp186Glu
LRG_274t1:c.681C>G
LRG_274:g.21207C>G
LRG_274p1:p.Asp227Glu
NC_000019.9:g.11216263C>G
NM_000527.4:c.681C>G
NM_001195798.1:c.681C>G
P01130:p.Asp227Glu
c.681C>G
p.(Asp227Glu)

Protein change:

D186E; ASP206GLU

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001815; UniProtKB: P01130#VAR_005338; OMIM: 606945.0006; dbSNP: rs121908028

Molecular consequence:

NM_001195800.2:c.314-1805C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-978C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.681C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.681C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.558C>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hypercholesterolemia, familial, 1
Synonyms:: LDL RECEPTOR DISORDER; Hyperlipoproteinemia Type IIa; HYPER-LOW-DENSITY-LIPOPROTEINEMIA; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007750; MedGen: C0745103; Orphanet: 391665; OMIM: 143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000024041	OMIM	no assertion criteria provided	Pathogenic (Jan 1, 2001)	germline	literature only	PubMed (5) [See all records that cite these PMIDs] 2352257, 1952806, 3425583, 3263645, 11491306
SCV000268580	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital See additional submitters Shariant Australia, Australian Genomics	no assertion criteria provided (ACMG Guidelines, 2015)	Pathogenic (Sep 11, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000294902	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (8) [See all records that cite these PMIDs] 11810272, 2569482, 15199436, 7718024, 8093663, 9664576, 21310417, 26892515 Citation Link,
SCV000484734	Robarts Research Institute, Western University	criteria provided, single submitter (Wang et al. (Arterioscler Thromb Vasc Biol. 2016))	Likely pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000503215	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 16, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000583721	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 30, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000599342	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 1, 2016)	germline, not applicable	curation, literature only	PubMed (2) [See all records that cite these PMIDs] 25741868, 1301956
SCV000606198	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV000731597	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 29, 2022)	germline	clinical testing	PubMed (18) [See all records that cite these PMIDs] 23375686, 8093663, 17087781, 8399083, 11810272, 2569482, 26892515, 9664576, 2352257, 3202825, 28965616, 21382890, 31345425, 31048103, 30270076, 30592178, 29284604, 25741868
SCV000748135	Iberoamerican FH Network	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 1, 2016)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 1301956
SCV001190761	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	no assertion criteria provided	Likely pathogenic (Feb 5, 2020)	germline	clinical testing
SCV001432571	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 5, 2019)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 31345425
SCV001653604	Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 24, 2021)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 2569482, 23375686, 32977124, 32041611, 28965616, 30710474, 31447099, 32922439, 30592178, 25741868
SCV002768391	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 21, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003827695	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 26, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004175303	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 27, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004807552	Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 29, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004820196	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 10, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 1301956, 1463746, 2352257, 2569482, 3202825, 6324732, 11491306, 25741868
SCV005903150	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Pathogenic (Apr 29, 2022)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV007595391	Variantyx, Inc.	criteria provided, single submitter (Variantyx Assertion Criteria 2022)	Likely Pathogenic (Aug 20, 2025)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 2569482, 29284604 Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	30	4	not provided	2616	not provided	clinical testing, literature only, research
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing, research, curation
not provided	not applicable	not applicable	not provided	not provided	not provided	not provided	not provided	literature only
Caucasian	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The molecular basis and diagnosis of familial hypercholesterolaemia in South African Afrikaners.

Kotze MJ, Langenhoven E, Warnich L, du Plessis L, Retief AE.

Ann Hum Genet. 1991 May;55(2):115-21.

PubMed [citation]

PMID:: 1952806

The longest-lived patient with homozygous familial hypercholesterolemia secondary to a defect in internalization of the LDL receptor.

Komuro I, Kato H, Nakagawa T, Takahashi K, Mimori A, Takeuchi F, Nishida Y, Miyamoto T.

Am J Med Sci. 1987 Nov;294(5):341-5.

PubMed [citation]

PMID:: 3425583

See all PubMed Citations (34)

Details of each submission

From OMIM, SCV000024041.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (5)

Description

Kotze et al. (1990) demonstrated a cytosine-to-guanine base substitution at nucleotide 681 resulting in an amino acid change from aspartic acid to glutamic acid at residue 206 (D206E) in the cysteine-rich ligand-binding domain of the LDL receptor. The mutation gives rise to an additional DdeI restriction site; segregation of the mutation with the disease was confirmed in 5 large Afrikaner FH (FHCL1; 143890) families. Kotze et al. (1990) predicted that 65% of affected South African Afrikaners carry this particular base substitution which can be diagnosed by PCR amplification of genomic DNA followed by restriction enzyme analysis. Indeed, from analysis of 138 chromosomes of Afrikaner FH patients, Kotze et al. (1991) found this mutation in 91 (68.4%). Komuro et al. (1987) described a homozygote for defective internalization of the LDL receptor who survived to age 57. Leitersdorf and Hobbs (1990) found the same mutation in an English American living in Maine.

Vergotine et al. (2001) demonstrated the feasibility of prenatal diagnosis of homozygous familial hypercholesterolemia in an Afrikaner family with the D206E mutation.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital, SCV000268580.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From LDLR-LOVD, British Heart Foundation, SCV000294902.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (8)
2	not provided	1	not provided	not provided	literature only	PubMed (8)
3	not provided	1	not provided	not provided	literature only	PubMed (8)
4	not provided	1	not provided	not provided	literature only	PubMed (8)
5	not provided	1	not provided	not provided	literature only	PubMed (8)
6	not provided	1	not provided	not provided	literature only	PubMed (8)
7	not provided	1	not provided	not provided	literature only	PubMed (8)
8	not provided	1	not provided	not provided	literature only	PubMed (8)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
2	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
3	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
4	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
5	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
6	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
7	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
8	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Robarts Research Institute, Western University, SCV000484734.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		2	not provided	not provided	not provided

From Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix, SCV000503215.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	6	not provided	not provided	clinical testing	PubMed (1)

Description

subjects mutated among 2600 FH index cases screened = 6 , family members = 3 with co-segregation / FH-Afrikaner-1 / Software predictions: Damaging

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	2600	not provided	not provided		6	not provided	not provided	not provided

From U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, SCV000583721.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	6	not provided	not provided	clinical testing	PubMed (1)

Description

Dutch Lipid Clinic Scoring : Definite FH

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		6	not provided	4	not provided

From Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, SCV000599342.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (2)
2	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

"Assay Description:Hmz patients' fibroblasts, 125I-LDL assays"

PubMed [ID: 1301956]

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided
2	not applicable	not applicable	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606198.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000731597.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (18)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Iberoamerican FH Network, SCV000748135.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (2)
2	not provided	not provided	not provided	not provided	research	PubMed (2)

Description

"Assay Description:Hmz patients' fibroblasts, 125I-LDL assays"

PubMed [ID: 1301956]

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided
2	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City, SCV001190761.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia, SCV001432571.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (2)
2	not provided	1	not provided	not provided	research	PubMed (2)
3	not provided	1	not provided	not provided	research	PubMed (2)
4	not provided	1	not provided	not provided	research	PubMed (2)
5	not provided	1	not provided	not provided	research	PubMed (2)
6	not provided	1	not provided	not provided	research	PubMed (2)
7	not provided	1	not provided	not provided	research	PubMed (2)
8	not provided	1	not provided	not provided	research	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
2	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
3	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
4	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
5	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
6	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
7	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
8	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II, SCV001653604.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	1	not provided	not provided	clinical testing	PubMed (10)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002768391.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV003827695.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genetics and Molecular Pathology, SA Pathology, SCV004175303.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre, SCV004807552.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004820196.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (8)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

From ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV005903150.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Variantyx, Inc., SCV007595391.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jul 27, 2026

Relating variation to medicine