NM_000527.5(LDLR):c.682G>C (p.Glu228Gln) AND Hypercholesterolemia, familial, 1

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Mar 30, 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:: RCV000237530.9

Allele description [Variation Report for NM_000527.5(LDLR):c.682G>C (p.Glu228Gln)]

NM_000527.5(LDLR):c.682G>C (p.Glu228Gln)

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>C (p.Glu228Gln)

Other names:

FH Tulsa-2; FH Iraq

HGVS:

NC_000019.10:g.11105588G>C
NG_009060.1:g.21208G>C
NM_000527.5:c.682G>CMANE SELECT
NM_001195798.2:c.682G>C
NM_001195799.2:c.559G>C
NM_001195800.2:c.314-1804G>C
NM_001195803.2:c.314-977G>C
NP_000518.1:p.Glu228Gln
NP_000518.1:p.Glu228Gln
NP_001182727.1:p.Glu228Gln
NP_001182728.1:p.Glu187Gln
LRG_274t1:c.682G>C
LRG_274:g.21208G>C
LRG_274p1:p.Glu228Gln
NC_000019.9:g.11216264G>C
NM_000527.4:c.682G>C
P01130:p.Glu228Gln
c.682G>C

Protein change:

E187Q

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001817; UniProtKB: P01130#VAR_005340

Molecular consequence:

NM_001195800.2:c.314-1804G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-977G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.682G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.682G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.559G>C - 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
SCV000294906	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (5) [See all records that cite these PMIDs] 1301956, 15199436, 16250003, 16389549, 8882879 Citation Link,
SCV000540753	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation See additional submitters Centre of Molecular Biology and Gene Therapy, University Hospital Brno	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 5, 2016)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000583725	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]
SCV000588512	Laboratory of Genetics and Molecular Cardiology, University of São Paulo - HipercolBrasil	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 1, 2016)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 1301956
SCV000606202	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV004812568	Molecular Genetics, Royal Melbourne Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 30, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 8599353, 25461735, 29720182, 32331935, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	8	1	not provided	5	not provided	clinical testing, literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	research
Caucasian	unknown	yes	1	1	not provided	3964	not provided	clinical testing

Citations

PubMed

Application of molecular genetics for diagnosing familial hypercholesterolemia in Norway: results from a family-based screening program.

Leren TP, Manshaus T, Skovholt U, Skodje T, Nossen IE, Teie C, Sørensen S, Bakken KS.

Semin Vasc Med. 2004 Feb;4(1):75-85. Review.

PubMed [citation]

PMID:: 15199436

Update of the molecular basis of familial hypercholesterolemia in The Netherlands.

Fouchier SW, Kastelein JJ, Defesche JC.

Hum Mutat. 2005 Dec;26(6):550-6.

PubMed [citation]

PMID:: 16250003

See all PubMed Citations (10)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000294906.2

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

#	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

From Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, SCV000540753.1

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

Description

Disrupt SDE motif. SDE bind structural Ca2+.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	3964	Whole blood	not provided		1	not provided	1	not provided

From U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, SCV000583725.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	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		3	not provided	1	not provided

From Laboratory of Genetics and Molecular Cardiology, University of São Paulo - HipercolBrasil, SCV000588512.1

#	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

%MAF(ExAC):0.0008547

"Assay description:Comp Htz (with p.(Asp221_Asp227dup)) 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 Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606202.1

#	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 Molecular Genetics, Royal Melbourne Hospital, SCV004812568.1

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

Description

This sequence change in LDLR is predicted to replace glutamic acid with glutamine at codon 228, p.(Glu228Gln) (also known as FH Tulsa-2, FH Iraq, and p.Glu207Gln). The glutamic acid residue is highly conserved (100 vertebrates, UCSC), and is located in the LDL-receptor class A repeat 5 of the ligand-binding domain. Exon 4 (amino acids 105-232) where this variant is located, is defined as a mutational hotspot in LDLR. There is a small physicochemical difference between glutamic acid and glutamine. The highest population minor allele frequency in the population database gnomAD v3.1 is 0.01% (5/41,458 alleles) in the African/African American population, which is consistent with familial hypercholesterolaemia (FH). This is a recurrent variant that has been reported in multiple probands with FH and segregates with disease in at least one family (PMID: 25461735, 29720182, 32331935). This variant has been observed in trans with the variant c.663_683dup, p.(Asp221_Asp227dup) (PMID: 8599353) which is classified as pathogenic (ClinVar ID: 251358) in an individual with homozygous FH. Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Another missense variant c.682G>A, p.(Glu228Lys) in the same codon (with a similar physicochemical difference) has been classified as pathogenic for FH (ClinVar ID: 3691). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PM1, PM3, PM5, PS4_Supporting, PM2_Supporting, PP1, PP3.

#	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

Last Updated: Oct 8, 2024

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