NM_000527.5(LDLR):c.1510A>G (p.Lys504Glu) AND Hypercholesterolemia, familial, 1

Germline classification:: Conflicting classifications of pathogenicity (6 submissions)
Last evaluated:: Jun 9, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000237290.13

Allele description [Variation Report for NM_000527.5(LDLR):c.1510A>G (p.Lys504Glu)]

NM_000527.5(LDLR):c.1510A>G (p.Lys504Glu)

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.1510A>G (p.Lys504Glu)

HGVS:

NC_000019.10:g.11113686A>G
NG_009060.1:g.29306A>G
NM_000527.5:c.1510A>GMANE SELECT
NM_001195798.2:c.1510A>G
NM_001195799.2:c.1387A>G
NM_001195800.2:c.1006A>G
NM_001195803.2:c.1129A>G
NP_000518.1:p.Lys504Glu
NP_000518.1:p.Lys504Glu
NP_001182727.1:p.Lys504Glu
NP_001182728.1:p.Lys463Glu
NP_001182729.1:p.Lys336Glu
NP_001182732.1:p.Lys377Glu
LRG_274t1:c.1510A>G
LRG_274:g.29306A>G
NC_000019.9:g.11224362A>G
NM_000527.4(LDLR):c.1510A>G
NM_000527.4:c.1510A>G
c.1510A>G

Protein change:

K336E

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001446; dbSNP: rs730882103

NCBI 1000 Genomes Browser:

rs730882103

Molecular consequence:

NM_000527.5:c.1510A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1510A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1387A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1006A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1129A>G - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

no known functional consequence - Comment(s)

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
SCV000295475	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely benign (Mar 25, 2016)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 19318025, 15199436 Citation Link,
SCV000503360	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)	Uncertain significance (Dec 16, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000583841	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 31, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 34906454, 25741868
SCV000606446	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Benign	germline	research
SCV000607606	Fundacion Hipercolesterolemia Familiar - SAFEHEART	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 1, 2016)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV004822467	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jun 9, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 15199436, 25487149, 25647241, 27784735, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	6	not provided	not provided	143475	not provided	clinical testing, research
not provided	germline	yes	6	2	not provided	2602	not provided	clinical testing, literature only

Citations

PubMed

Genetic diagnosis of familial hypercholesterolemia using a DNA-array based platform.

Alonso R, Defesche JC, Tejedor D, Castillo S, Stef M, Mata N, Gomez-Enterria P, Martinez-Faedo C, Forga L, Mata P.

Clin Biochem. 2009 Jun;42(9):899-903. doi: 10.1016/j.clinbiochem.2009.01.017. Epub 2009 Feb 6.

PubMed [citation]

PMID:: 19318025

The Clinical Genome Resource (ClinGen) Familial Hypercholesterolemia Variant Curation Expert Panel consensus guidelines for LDLR variant classification.

Chora JR, Iacocca MA, Tichý L, Wand H, Kurtz CL, Zimmermann H, Leon A, Williams M, Humphries SE, Hooper AJ, Trinder M, Brunham LR, Costa Pereira A, Jannes CE, Chen M, Chonis J, Wang J, Kim S, Johnston T, Soucek P, Kramarek M, Leigh SE, et al.

Genet Med. 2022 Feb;24(2):293-306. doi: 10.1016/j.gim.2021.09.012. Epub 2021 Nov 30.

PubMed [citation]

PMID:: 34906454

See all PubMed Citations (7)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295475.2

#	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, SCV000503360.1

#	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: Benign

#	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 U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, SCV000583841.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (2)

Description

Dutch Lipid Clinic Scoring : Probable FH

Description

This missense variant LDLR: c.1510A>G (p.Lys504Glu), replaces lysine with glutamic acid at codon 504 of the LDLR protein. According to updated genomic data and to ClinGen FH VCEP criteria issued in 2022 (PMID: 34906454) for the validation of pathogenicity of LDLR variants, this variant may now be classified as “Variant of Uncertain Significance” from conflicting evidence as follows. This variant is located within a conserved (REVEL=0.529) functional domain (LDLR Class B3) involved in LDL receptor recycling to the plasma membrane (PP3-supporting). This variant is observed with a frequency <0.02% (PM2), in the general population (GnomAD= 0.0000197, no homozygotes). It was observed in hypercholesterolemic individuals and reported to cosegregate with FH in independent families of European ancestry (PS4-supporting). However, level 1 in-vitro functional studies have shown that this variant has a neutral effect on LDLR function (BS3).

#	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	2	not provided

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606446.1

#	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 Fundacion Hipercolesterolemia Familiar - SAFEHEART, SCV000607606.1

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

Description

%MAF(ExAC):0.004122

#	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 All of Us Research Program, National Institutes of Health, SCV004822467.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	6	not provided	not provided	clinical testing	PubMed (5)

Description

This missense variant (also known as p.Lys483Glu in the mature protein) replaces lysine with glutamic acid at codon 504 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A cell-based experimental study has shown that this variant does not disrupt LDL uptake function of the protein (PMID: 25647241). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 15199436, 25647241; Color internal data). This variant has also been observed in compound heterozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 27784735). Additionally, this variant has been reported in individuals affected with myocardial infarction (PMID: 25487149). This variant has been identified in 3/251454 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	143475	not provided	not provided		6	not provided	not provided	not provided

Last Updated: May 16, 2025

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