NM_000527.5(LDLR):c.769C>T (p.Arg257Trp) AND Hypercholesterolemia, familial, 1

Germline classification:: Conflicting interpretations of pathogenicity (9 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:: RCV000237953.15

Allele description [Variation Report for NM_000527.5(LDLR):c.769C>T (p.Arg257Trp)]

NM_000527.5(LDLR):c.769C>T (p.Arg257Trp)

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.769C>T (p.Arg257Trp)

HGVS:

NC_000019.10:g.11106639C>T
NG_009060.1:g.22259C>T
NM_000527.5:c.769C>TMANE SELECT
NM_001195798.2:c.769C>T
NM_001195799.2:c.646C>T
NM_001195800.2:c.314-753C>T
NM_001195803.2:c.388C>T
NP_000518.1:p.Arg257Trp
NP_000518.1:p.Arg257Trp
NP_001182727.1:p.Arg257Trp
NP_001182728.1:p.Arg216Trp
NP_001182732.1:p.Arg130Trp
LRG_274t1:c.769C>T
LRG_274:g.22259C>T
LRG_274p1:p.Arg257Trp
NC_000019.9:g.11217315C>T
NM_000527.4:c.769C>T
P01130:p.Arg257Trp
c.769C>T

Protein change:

R130W

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000115; UniProtKB: P01130#VAR_072836

Molecular consequence:

NM_001195800.2:c.314-753C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.769C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.769C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.646C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.388C>T - 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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Rattus norvegicus minichromosome maintenance complex component 3 associated prot...
Rattus norvegicus minichromosome maintenance complex component 3 associated protein (Mcm3ap), mRNA
gi|157822500|ref|NM_001106382.1|

Nucleotide
Cambridgea pallidula voucher NZAC03014773 cytochrome c oxidase subunit 1 (COI) g...
Cambridgea pallidula voucher NZAC03014773 cytochrome c oxidase subunit 1 (COI) gene, partial cds; mitochondrial
gi|1735127408|gb|MK910929.1|

Nucleotide
LOC106104083 [Papilio polytes]
LOC106104083 [Papilio polytes]
Gene ID:106104083

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000294964	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely benign (Mar 25, 2016)	germline	literature only	PubMed (6) [See all records that cite these PMIDs] 11462246, 11933210, 16250003, 20538126, 19318025, 26343872 Citation Link,
SCV000503232	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]
SCV000583738	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Jan 31, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] PMID: 34906454,
SCV000588517	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 (2) [See all records that cite these PMIDs] 25741868, 25545329
SCV000606221	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV000607499	Fundacion Hipercolesterolemia Familiar - SAFEHEART	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 1, 2016)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 25545329
SCV000782953	Robarts Research Institute, Western University	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 2, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001432577	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 3, 2019)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 31345425
SCV004820210	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 13, 2023)	germline	clinical testing	PubMed (17) [See all records that cite these PMIDs] 11462246, 11933210, 16250003, 18325082, 20538126, 22353362, 25461735, 25545329, 25962062, 26343872, 29399563, 32759540, 33994402, 34456200, 34573395, 35137788, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	10	1	not provided	2607	not provided	clinical testing, literature only, research
not provided	germline	unknown	11	not provided	not provided	108544	not provided	clinical testing, research

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

Risk of Premature Atherosclerotic Disease in Patients With Monogenic Versus Polygenic Familial Hypercholesterolemia.

Trinder M, Li X, DeCastro ML, Cermakova L, Sadananda S, Jackson LM, Azizi H, Mancini GBJ, Francis GA, Frohlich J, Brunham LR.

J Am Coll Cardiol. 2019 Jul 30;74(4):512-522. doi: 10.1016/j.jacc.2019.05.043.

PubMed [citation]

PMID:: 31345425

See all PubMed Citations (19)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000294964.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (6)
2	not provided	1	not provided	not provided	literature only	PubMed (6)
3	not provided	1	not provided	not provided	literature only	PubMed (6)
4	not provided	1	not provided	not provided	literature only	PubMed (6)
5	not provided	1	not provided	not provided	literature only	PubMed (6)
6	not provided	1	not provided	not provided	literature only	PubMed (6)

#	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
6	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, SCV000503232.1

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

Description

subjects mutated among 2600 FH index cases screened = 2 / in association with c.1765G>A, p.Asp589Asn / 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		2	not provided	not provided	not provided

From U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, SCV000583738.2

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

Description

Dutch Lipid Clinic Scoring : Definite FH

Description

This missense variant LDLR:c.769C>T (also known as p.Arg236Trp in the mature protein), replaces a arginine with tryptophan at codon 257 of the LDLR protein (p.Arg257Trp). 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 reclassified as “Likely Benign” from evidence as follows. It is located within a conserved (REVEL=0.648) functional domain (LDLR Class A6) involved in LDL binding with LDL receptors. Because this variant is observed with a frequency <0.02% in the general population (GnomAD= 0.0000985, no homozygotes) multiple reports classify this variant as VUS (PM2). However, despite apparent cosegregation in several independent FH families, it has been frequently observed in normolipidemic individuals (BS2) or in Cis with other proven pathogenic variants in FH patients (BP2). Finally, several independent level 1 in-vitro functional studies have shown consistently 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		1	not provided	1	not provided

From Laboratory of Genetics and Molecular Cardiology, University of São Paulo - HipercolBrasil, SCV000588517.1

#	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):0.007414

"Assay description:Heterologous cells (CHO), FACS assays"

PubMed [ID: 25545329]

#	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, SCV000606221.1

#	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, SCV000607499.1

#	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):0.007414

"Heterologous cells (CHO), FACS assays"

PubMed [ID: 25545329]

#	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 Robarts Research Institute, Western University, SCV000782953.1

#	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	yes	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, SCV001432577.1

#	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 All of Us Research Program, National Institutes of Health, SCV004820210.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	11	not provided	not provided	clinical testing	PubMed (17)

Description

This missense variant (also known as p.Arg236Trp in the mature protein) is located in the sixth LDLR type A repeat in the ligand binding domain 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). Functional studies have demonstrated that the variant protein shows normal LDLR expression at the cell surface and normal LDL binding and uptake activity (PMID: 25545329). This variant has been reported in many individuals affected with or suspected of having familial hypercholesterolemia in Brazil, China, Germany, Korea and the Netherlands (PMID: 11462246, 11933210, 16250003, 20538126, 22353362, 25461735, 25962062, 26343872, 32759540, 33994402, 34456200, 34573395, 35137788). In two Chinese brothers with severe hypercholesterolemia, this variant co-occurred with two other heterozygous variants in LDLR (p.Gln191* and p.Asp589Asn) (PMID: 29399563). This variant and p.Asp589Asn have been reported to occur on the same allele (PMID: 16250003, 18325082). This variant has been identified in 26/282894 chromosomes (20/19954 East Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Functional studies and relatively high allele frequency in the general population indicate that this variant is unlikely to cause disease. However, additional studies are necessary 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	108544	not provided	not provided		11	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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