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

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Jan 31, 2024
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:: RCV000775232.16

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:: Familial hypercholesterolemia
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000544645	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 2318961, 21475731, 21722902, 22390909, 23375686, 18677035, 1301956, 8882879, 16250003, 17094996, 28492532
SCV000909484	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 22, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000919585	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 30, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23375686, 9484998 Citation Link,
SCV001482466	Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	germline	research	PubMed (2) [See all records that cite these PMIDs] 29261184, 25741868
SCV002086382	Natera, Inc.	no assertion criteria provided	Pathogenic (Feb 4, 2021)	germline	clinical testing

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
not provided	germline	yes	1	not provided	not provided	1	not provided	research

Citations

PubMed

Common low-density lipoprotein receptor mutations in the French Canadian population.

Leitersdorf E, Tobin EJ, Davignon J, Hobbs HH.

J Clin Invest. 1990 Apr;85(4):1014-23.

PubMed [citation]

PMID:: 2318961
PMCID:: PMC296530

Founder mutations in the Netherlands: geographical distribution of the most prevalent mutations in the low-density lipoprotein receptor and apolipoprotein B genes.

Kusters DM, Huijgen R, Defesche JC, Vissers MN, Kindt I, Hutten BA, Kastelein JJ.

Neth Heart J. 2011 Apr;19(4):175-182. Epub 2011 Jan 27.

PubMed [citation]

PMID:: 21475731
PMCID:: PMC3058324

See all PubMed Citations (14)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000544645.9

#	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 glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 228 of the LDLR protein (p.Glu228Lys). This variant is present in population databases (rs121908029, gnomAD 0.01%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 2318961, 21475731, 21722902, 22390909, 23375686). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Glu207Lys. ClinVar contains an entry for this variant (Variation ID: 3691). 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: 18677035). This variant disrupts the p.Glu228 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301956, 8882879, 16250003, 17094996). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 Color Diagnostics, LLC DBA Color Health, SCV000909484.3

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

Description

This variant (also known as p.Glu207Lys in the mature protein and as FH Canadian-3, FH Modena, and FH Mexico-3) is a missense variant located in the fifth LDLR type A repeat of the ligand binding domain of the LDLR protein that forms a calcium binding pocket. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. In experimental studies, the mutant protein has shown normal LDL binding affinity but reduced affinity for _x0001_beta-VLDL (PMID: 18677035) and delayed processing to the mature form (PMID: 2318961). This has been identified in numerous individuals diagnosed with familial hypercholesterolemia (PMID: 2318961, 15359125, 21475731, 21722902, 22390909, 23375686). This variant has been identified in 4/247898 chromosomes by the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely 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, SCV000919585.1

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

Description

Variant summary: LDLR c.682G>A (p.Glu228Lys) results in a conservative amino acid change located in the Low-density lipoprotein (LDL) receptor class A repeat 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 1.6e-05 in 244390 control chromosomes. c.682G>A has been reported in the literature in numerous individuals affected with Familial Hypercholesterolemia. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, showing the variant to result in impaired lipoprotein binding (Hobbs_1992). In addition, other variants at this codon have been reported as pathogenic (p.Glu228Gln, p.Glu228X). 12 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. 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 Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine, SCV001482466.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	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

From Natera, Inc., SCV002086382.1

#	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

Last Updated: Oct 20, 2024

ClinVar

Relating variation to medicine