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

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jun 7, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV002362555.5

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:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002664715	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jun 7, 2024)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 11810272, 1301956, 1463746, 15199436, 21310417, 26892515, 27765764, 28965616, 30592178, 3202825, 8093663, 9664576 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002664715

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jun 7, 2024)

germline

clinical testing

PubMed (12)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

The molecular basis of familial hypercholesterolemia in The Netherlands.

Fouchier SW, Defesche JC, Umans-Eckenhausen MW, Kastelein JP.

Hum Genet. 2001 Dec;109(6):602-15. Epub 2001 Nov 9.

PubMed [citation]

PMID:: 11810272

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

See all PubMed Citations (12)

Details of each submission

From Ambry Genetics, SCV002664715.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

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.

#	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: Oct 13, 2024

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