NM_000527.5(LDLR):c.2441G>A (p.Arg814Gln) AND Hypercholesterolemia, familial, 1

Germline classification:: Conflicting interpretations of pathogenicity (6 submissions)
Last evaluated:: Jan 31, 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:: RCV000237126.20

Allele description [Variation Report for NM_000527.5(LDLR):c.2441G>A (p.Arg814Gln)]

NM_000527.5(LDLR):c.2441G>A (p.Arg814Gln)

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.2441G>A (p.Arg814Gln)

Other names:

FH Xhosa

HGVS:

NC_000019.10:g.11129564G>A
NG_009060.1:g.45184G>A
NM_000527.5:c.2441G>AMANE SELECT
NM_001195798.2:c.2441G>A
NM_001195799.2:c.2318G>A
NM_001195800.2:c.1937G>A
NM_001195803.2:c.1907G>A
NP_000518.1:p.Arg814Gln
NP_000518.1:p.Arg814Gln
NP_001182727.1:p.Arg814Gln
NP_001182728.1:p.Arg773Gln
NP_001182729.1:p.Arg646Gln
NP_001182732.1:p.Arg636Gln
LRG_274t1:c.2441G>A
LRG_274:g.45184G>A
LRG_274p1:p.Arg814Gln
NC_000019.9:g.11240240G>A
NM_000527.4:c.2441G>A
P01130:p.Arg814Gln
c.2441G>A

Protein change:

R636Q

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000376; UniProtKB: P01130#VAR_011864

Molecular consequence:

NM_000527.5:c.2441G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.2441G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.2318G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1937G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1907G>A - 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
SCV000296010	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely benign (Mar 25, 2016)	germline	literature only	PubMed (4) [See all records that cite these PMIDs] 10882754, 16250003, 16389549, 9544746 Citation Link,
SCV000503489	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 benign (Dec 16, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000583953	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 34906454, 25741868
SCV000588667	Laboratory of Genetics and Molecular Cardiology, University of São Paulo - HipercolBrasil	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 1, 2016)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV000606653	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV002764304	New York Genome Center	criteria provided, single submitter (NYGC Assertion Criteria 2020)	Uncertain significance (Jul 2, 2021)	germline	clinical testing	Citation Link

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	2604	not provided	clinical testing, literature only
not provided	germline	unknown	1	not provided	not provided	1	not provided	research, clinical testing

Citations

PubMed

Predominance of a 6 bp deletion in exon 2 of the LDL receptor gene in Africans with familial hypercholesterolaemia.

Thiart R, Scholtz CL, Vergotine J, Hoogendijk CF, de Villiers JN, Nissen H, Brusgaard K, Gaffney D, Hoffs MS, Vermaak WJ, Kotze MJ.

J Med Genet. 2000 Jul;37(7):514-9.

PubMed [citation]

PMID:: 10882754
PMCID:: PMC1734636

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 (6)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000296010.2

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

#	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

From Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix, SCV000503489.1

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

Description

subjects mutated among 2600 FH index cases screened = 3 , family member = 1/previously described in association with FH/Software predictions: Conflicting

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	2600	not provided	not provided		3	not provided	not provided	not provided

From U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, SCV000583953.2

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

Description

Dutch Lipid Clinic Scoring : Probable FH

Description

This missense variant LDLR c.2441G>A (also known as p.Arg793Gln in the mature protein), replaces an arginine with glutamine at codon 814 of the LDLR protein (p.Arg814Gln). 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 “Likely Pathogenic” from evidence as follows. It is located within a highly conserved functional domain (Cytoplasmic domain) essential for LDLR internalization. This variant was historically assessed in-vivo (PM3) and in-vitro in homozygous FH (PS3-moderate), observed as a founder mutation for FH (PS4) or a polymorphism at risk of hypercholesterolemia in populations of African ancestry, and was estimated as pathogenic in-silico (REVEL= 0,768) by disrupting a domain required for MYLIP-triggered down-regulation of LDLR (PP3). However, discrepant observations in mildly hypercholesterolemic or normolipidemic subjects, a high frequency in the general population (GnomAD= 0.00111, with no homozygotes) and lack of high-level in-vitro functional studies lead to classify this variant as “Likely Pathogenic” with low penetrance.

#	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		1	not provided	1	not provided

From Laboratory of Genetics and Molecular Cardiology, University of São Paulo - HipercolBrasil, SCV000588667.1

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

Description

%MAF(ExAC):0.02801

#	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 Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606653.1

#	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 New York Genome Center, SCV002764304.1

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

Description

The c.2441G>A (p.Arg814Gln) variant identified in the LDLR gene substitutes a moderately conserved Arginine for Glutamine at amino acid 814/861(exon 17/18). This variant is found with appreciable frequency in gnomAD(v3.1.1), including in two homozygotes (168 heterozygotes, 2 homozygotes; allele frequency:1.11e-3), which is higher than expected for a pathogenic variant in the LDLR gene. The c.2441G>A (p.Arg814Gln) variant is reported in ClinVar as Pathogenic, Likely Pathogenic, Likely Benign, and as a Variant of Uncertain Significance (VarID:161278). This variant has been identified in many affected individuals in the literature, although its role in relation to hyperlipidemia in those individuals is not clearly defined [PMID:9544746, 10882754, 16389549, 27784735, 33508743]. In silico algorithms predict this variant to be Damaging (SIFT; score:0.00) and Pathogenic (REVEL; score:0.768) to the function of the canonical transcript. While the c.2441G>A(p.Arg814Gln) variant identified in the LDLR gene has been identified in many affected individuals in the literature and is predicted damaging by in silico predictors, its allele frequency is higher than expected. Given the conflicting evidence regarding its pathogenicity, the c.2441G>A (p.Arg814Gln) variant identified in the LDLR gene is reported 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	1	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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