NM_000527.5(LDLR):c.420G>C (p.Glu140Asp) AND Hypercholesterolemia, familial, 1

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: Feb 11, 2022
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:: RCV000237168.13

Allele description [Variation Report for NM_000527.5(LDLR):c.420G>C (p.Glu140Asp)]

NM_000527.5(LDLR):c.420G>C (p.Glu140Asp)

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.420G>C (p.Glu140Asp)

HGVS:

NC_000019.10:g.11105326G>C
NG_009060.1:g.20946G>C
NM_000527.5:c.420G>CMANE SELECT
NM_001195798.2:c.420G>C
NM_001195799.2:c.297G>C
NM_001195800.2:c.314-2066G>C
NM_001195803.2:c.314-1239G>C
NP_000518.1:p.Glu140Asp
NP_000518.1:p.Glu140Asp
NP_001182727.1:p.Glu140Asp
NP_001182728.1:p.Glu99Asp
LRG_274t1:c.420G>C
LRG_274:g.20946G>C
LRG_274p1:p.Glu140Asp
NC_000019.9:g.11216002G>C
NM_000527.4:c.420G>C
c.420G>C

Protein change:

E140D

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000057; dbSNP: rs879254520

NCBI 1000 Genomes Browser:

rs879254520

Molecular consequence:

NM_001195800.2:c.314-2066G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-1239G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.420G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.420G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.297G>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

Recent activity

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Terpenoid cyclases/Protein prenyltransferases superfamily protein [Arabidopsis t...
Terpenoid cyclases/Protein prenyltransferases superfamily protein [Arabidopsis thaliana]
gi|334184388|ref|NP_179904.3|

Protein
dapE [Burkholderia pseudomallei]
dapE [Burkholderia pseudomallei]
Gene ID:56529022

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000294701	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 11754108, 20145306 Citation Link,
SCV000503155	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 16, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000540732	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)	inherited	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25741868, 22698793, 11754108
SCV000606114	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV000839978	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 23, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001432649	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 5, 2019)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 31345425
SCV003829664	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 11, 2022)	germline	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	4	not provided	not provided	2603	not provided	clinical testing, literature only, research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, research
Caucasian	inherited	yes	10	7	not provided	3964	yes	clinical testing

Citations

PubMed

Molecular characterization of Polish patients with familial hypercholesterolemia: novel and recurrent LDLR mutations.

Chmara M, Wasag B, Zuk M, Kubalska J, Wegrzyn A, Bednarska-Makaruk M, Pronicka E, Wehr H, Defesche JC, Rynkiewicz A, Limon J.

J Appl Genet. 2010;51(1):95-106. doi: 10.1007/BF03195716.

PubMed [citation]

PMID:: 20145306

The molecular basis of familial hypercholesterolemia in the Czech Republic: spectrum of LDLR mutations and genotype-phenotype correlations.

Tichý L, Freiberger T, Zapletalová P, Soška V, Ravčuková B, Fajkusová L.

Atherosclerosis. 2012 Aug;223(2):401-8. doi: 10.1016/j.atherosclerosis.2012.05.014. Epub 2012 May 23.

PubMed [citation]

PMID:: 22698793

See all PubMed Citations (5)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000294701.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (2)
2	not provided	1	not provided	not provided	literature only	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
2	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix, SCV000503155.1

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

Description

subject mutated among 2600 FH index cases screened = 1 / Software predictions: Damaging

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	2600	not provided	not provided		1	not provided	not provided	not provided

From Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, SCV000540732.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	10	not provided	yes	clinical testing	PubMed (3)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	3964	Whole blood	not provided		10	not provided	7	not provided

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606114.1

#	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 Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV000839978.1

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

Description

This c.420G>C (p.Glu140Asp) variant in the LDLR gene has been reported in multiple individuals with familial hypercholesterolemia (PMID: 11754108, 20145306, 22698793, 23680767). A different variant at the same residue (p.Glu140Lys) has also been described in multiple individuals with familial hypercholesterolemia (PMID: 1301956, 11668627, 21722902, 23375686) The p.Glu140Asp variant occurs within the low-density lipoprotein receptor repeat class A domain of the LDLR protein (https://www.ncbi.nlm.nih.gov/Structure/cdd/wrpsb.cgi?seqinput=NP_001182729.1 ). The c.420G>C variant is not detected in the general population and glutamate at position 140 of the LDLR protein is highly evolutionarily conserved. The c.420G>C (p.Glu140Asp) variant in the LDLR gene 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 Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia, SCV001432649.1

#	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 Revvity Omics, Revvity, SCV003829664.2

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

#	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: Aug 11, 2024

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