NM_000527.5(LDLR):c.682G>A (p.Glu228Lys) AND Cardiovascular phenotype

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 17, 2022
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:: RCV002362556.2

Allele description [Variation Report for NM_000527.5(LDLR):c.682G>A (p.Glu228Lys)]

NM_000527.5(LDLR):c.682G>A (p.Glu228Lys)

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.682G>A (p.Glu228Lys)

Other names:

E207K; FH Mexico; FH French Canadian 3; FH Canadian-3; FH Modena; FH French Canadian-3; FH Mexico 3; NP_000518.1:p.E228K; NM_000527.5(LDLR):c.682G>A

HGVS:

NC_000019.10:g.11105588G>A
NG_009060.1:g.21208G>A
NM_000527.5:c.682G>AMANE SELECT
NM_001195798.2:c.682G>A
NM_001195799.2:c.559G>A
NM_001195800.2:c.314-1804G>A
NM_001195803.2:c.314-977G>A
NP_000518.1:p.Glu228Lys
NP_000518.1:p.Glu228Lys
NP_001182727.1:p.Glu228Lys
NP_001182728.1:p.Glu187Lys
LRG_274t1:c.682G>A
LRG_274:g.21208G>A
LRG_274p1:p.Glu228Lys
NC_000019.9:g.11216264G>A
NM_000527.4:c.682G>A
P01130:p.Glu228Lys
c.682G>A

Protein change:

E187K; GLU207LYS

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000105; UniProtKB: P01130#VAR_005341; OMIM: 606945.0007

Molecular consequence:

NM_001195800.2:c.314-1804G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-977G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.682G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.682G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.559G>A - 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
SCV002666629	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Aug 17, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 10978268, 12837857, 16183066, 22390909, 2318961, 23375686, 29399563 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002666629

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Aug 17, 2022)

germline

clinical testing

PubMed (7)
[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

Clinical expression of familial hypercholesterolemia in clusters of mutations of the LDL receptor gene that cause a receptor-defective or receptor-negative phenotype.

Bertolini S, Cantafora A, Averna M, Cortese C, Motti C, Martini S, Pes G, Postiglione A, Stefanutti C, Blotta I, Pisciotta L, Rolleri M, Langheim S, Ghisellini M, Rabbone I, Calandra S.

Arterioscler Thromb Vasc Biol. 2000 Sep;20(9):E41-52.

PubMed [citation]

PMID:: 10978268

Identification and characterization of LDL receptor gene mutations in hyperlipidemic Chinese.

Chang JH, Pan JP, Tai DY, Huang AC, Li PH, Ho HL, Hsieh HL, Chou SC, Lin WL, Lo E, Chang CY, Tseng J, Su MT, Lee-Chen GJ.

J Lipid Res. 2003 Oct;44(10):1850-8. Epub 2003 Jul 1.

PubMed [citation]

PMID:: 12837857

See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV002666629.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

The p.E228K pathogenic mutation (also known as c.682G>A), located in coding exon 4 of the LDLR gene, results from a G to A substitution at nucleotide position 682. The glutamic acid at codon 228 is replaced by lysine, an amino acid with similar properties. This alteration, historically described as p.E207K, FH French Canadian, FH Mexico-3, and FH-Modena, has been detected in numerous individuals with familial hypercholesterolemia (FH) across multiple ethnicities (Leitersdorf E et al. J. Clin. Invest., 1990 Apr;85:1014-23; Bertolini S et al. Arterioscler. Thromb. Vasc. Biol., 2000 Sep;20:E41-52; Kim HN et al. Chonnam Med J, 2018 Jan;54:31-35). Functional studies have demonstrated decreased amounts of mature mRNA, reduced protein transport from the endoplasmic reticulum, and LDLR activity that is 40-45% of wild-type levels (Leitersdorf E et al. J. Clin. Invest., 1990 Apr;85:1014-23; Bertolini S et al. Arterioscler. Thromb. Vasc. Biol., 2000 Sep;20:E41-52; Chang JH et al. J. Lipid Res., 2003 Oct;44:1850-8). Furthermore, an alternate nucleotide change at this position, c.682G>C p.E228Q (also known as p.E207Q, FH Tulsa-2, FH Iraq) has been well-described as a mutation in numerous individuals with FH, suggesting a likely hotspot location (Hobbs HH et al. Hum. Mutat., 1992;1:445-66). 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 20, 2024

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