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

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Dec 29, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000771320.17

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

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

NCBI 1000 Genomes Browser:

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]

Condition(s)

Name:: Familial hypercholesterolemia (FH)
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000903585	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 23, 2023)	germline	clinical testing	PubMed (24) [See all records that cite these PMIDs] 1301956, 1463746, 1952806, 2352257, 2569482, 3202825, 6324732, 7718024, 8093663, 9664576, 11491306, 11810272, 15199436, 17087781, 21310417, 23375686, 26892515, 27765764, 33955087, 33994402, 34037665, 34297352, 36229885, 25741868
SCV000940292	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 29, 2023)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 17539906, 19467224, 21310417, 21382890, 22883975, 23375686, 23669246, 27680772, 2352257, 2569482, 28492532
SCV001361870	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 24, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 7947594, 23375686, 26892515, 2569482, 2352257, 29284604 Citation Link,
SCV002086381	Natera, Inc.	no assertion criteria provided	Pathogenic (Dec 2, 2020)	germline	clinical testing
SCV004123055	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 1, 2023)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV005045761	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 30, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular genetics of the LDL receptor gene in familial hypercholesterolemia.

Hobbs HH, Brown MS, Goldstein JL.

Hum Mutat. 1992;1(6):445-66. Review.

PubMed [citation]

PMID:: 1301956

Low-density lipoprotein receptor point mutation results in expression of both active and inactive surface forms of the same mutant receptor.

Fourie AM, Coetzee GA, Gevers W, van der Westhuyzen DR.

Biochemistry. 1992 Dec 29;31(51):12754-9.

PubMed [citation]

PMID:: 1463746

See all PubMed Citations (33)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000903585.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (24)

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, 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.

#	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 Invitae, SCV000940292.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

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). This variant is also known as Asp206Glu and FH Afrikaner-1. ClinVar contains an entry for this variant (Variation ID: 3690). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001361870.2

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

Description

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.

#	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 Natera, Inc., SCV002086381.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand, SCV004123055.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	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 Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV005045761.1

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

Description

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.

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

Last Updated: Jun 17, 2024

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