NM_000527.5(LDLR):c.259T>G (p.Trp87Gly) AND Hypercholesterolemia, familial, 1

Germline classification:: Pathogenic (16 submissions)
Last evaluated:: Jun 7, 2021
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000003870.42

Allele description [Variation Report for NM_000527.5(LDLR):c.259T>G (p.Trp87Gly)]

NM_000527.5(LDLR):c.259T>G (p.Trp87Gly)

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.259T>G (p.Trp87Gly)

Other names:

W66G; FH French Canadian 4; NP_000518.1:p.W87G; NM_000527.5(LDLR):c.259T>G

HGVS:

NC_000019.10:g.11102732T>G
NG_009060.1:g.18352T>G
NM_000527.5:c.259T>GMANE SELECT
NM_001195798.2:c.259T>G
NM_001195799.2:c.190+2387T>G
NM_001195800.2:c.259T>G
NM_001195803.2:c.259T>G
NP_000518.1:p.Trp87Gly
NP_000518.1:p.Trp87Gly
NP_001182727.1:p.Trp87Gly
NP_001182729.1:p.Trp87Gly
NP_001182732.1:p.Trp87Gly
LRG_274t1:c.259T>G
LRG_274:g.18352T>G
LRG_274p1:p.Trp87Gly
NC_000019.9:g.11213408T>G
NM_000527.4:c.259T>G
P01130:p.Trp87Gly
c.259T>G

Protein change:

W87G; TRP66GLY

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001671; UniProtKB: P01130#VAR_005308; OMIM: 606945.0003; dbSNP: rs121908025

NCBI 1000 Genomes Browser:

rs121908025

Molecular consequence:

NM_001195799.2:c.190+2387T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.259T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.259T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.259T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.259T>G - 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
SCV000024035	OMIM	no assertion criteria provided	Pathogenic (Apr 1, 1994)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 2318961, 8098448, 8054972
SCV000268547	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	no assertion criteria provided	Pathogenic (Dec 18, 2008)	germline	clinical testing
SCV000294560	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] 2318961, 8645371, 9104431, 9259195, 9676383 Citation Link,
SCV000484716	Robarts Research Institute, Western University	criteria provided, single submitter (Wang et al. (Arterioscler Thromb Vasc Biol. 2016))	Likely pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000503120	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]
SCV000540721	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 (1) [See all records that cite this PMID]
SCV000583644	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]
SCV000606051	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV001428736	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 6, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001432641	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 13, 2019)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 31345425
SCV001711949	Johns Hopkins Genomics, Johns Hopkins University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 28, 2021)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 10735631, 12553167, 16542394, 2318961, 9272705, 25741868
SCV001754778	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 4, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001960956	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-1)	Pathogenic (Jun 7, 2021)	germline	curation	Citation Link,
SCV002017127	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 14, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002061569	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 20, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004820136	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 18, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 2318961, 8098448, 9104431, 9259195, 9272705, 31578082, 33955087, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	46	5	not provided	2617	not provided	clinical testing, literature only, research
not provided	germline	unknown	4	not provided	not provided	143475	not provided	clinical testing, research, curation
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
Caucasian	inherited	yes	3	1	not provided	3964	yes	clinical testing

Citations

PubMed

Successful ex vivo gene therapy directed to liver in a patient with familial hypercholesterolaemia.

Grossman M, Raper SE, Kozarsky K, Stein EA, Engelhardt JF, Muller D, Lupien PJ, Wilson JM.

Nat Genet. 1994 Apr;6(4):335-41.

PubMed [citation]

PMID:: 8054972

The Trp23-Stop and Trp66-Gly mutations in the LDL receptor gene: common causes of familial hypercholesterolemia in Denmark.

Jensen HK, Jensen LG, Hansen PS, Faergeman O, Gregersen N.

Atherosclerosis. 1996 Feb;120(1-2):57-65.

PubMed [citation]

PMID:: 8645371

See all PubMed Citations (16)

Details of each submission

From OMIM, SCV000024035.3

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

Description

This change in exon 3 is a class 3 binding-defective mutation (Leitersdorf et al., 1990). In the French Canadian population of a province in Quebec, Moorjani et al. (1993) compared the clinical features of homozygous FH (FHCL1; 143890) because of the relatively high frequency of a small number of mutations. In a comparison of 10 subjects who had the trp66-to-gly (W66G) mutation in exon 3 with 11 subjects who were homozygous for the 'greater than 10 kb' deletion of the promoter region in exon 1 (606945.0025), they found the following: mean plasma cholesterol concentration was higher in the subjects with the deletion and there was no overlap in values in the 2 groups. Although the frequency of coronary heart disease was similar in the 2 groups, age of onset was earlier in subjects with the deletion; in addition, coronary deaths were more frequent and occurred at an earlier age in the deletion subjects.

Grossman et al. (1994) reported a 29-year-old woman with FH and a homozygous W66G mutation who underwent hepatocyte-directed ex vivo gene therapy with LDLR-expressing retroviruses. She tolerated the procedures well, liver biopsy after 4 months showed engraftment of the transgene, and there was no clinical or pathologic evidence for autoimmune hepatitis. The patient showed an improvement in serum lipids up to 18 months after the treatment.

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

From Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital, SCV000268547.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	6	not provided	not provided	clinical testing	not provided

#	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		6	not provided	not provided	not provided

From LDLR-LOVD, British Heart Foundation, SCV000294560.2

#	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 Robarts Research Institute, Western University, SCV000484716.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	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		3	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, SCV000503120.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	9	not provided	not provided	clinical testing	PubMed (1)

Description

subjects mutated among 2600 FH index cases screened = 9 , family members = 7 with co-segregation / frequently associated with c.1975A>C, p.Thr659Pro (2 index cases), Subnormal LDLR activity / 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		9	not provided	not provided	not provided

From Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, SCV000540721.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	3964	Whole blood	not provided		3	not provided	1	not provided

From U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, SCV000583644.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	11	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		11	not provided	5	not provided

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606051.1

#	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 Institute of Human Genetics, University of Leipzig Medical Center, SCV001428736.2

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

Description

Criteria applied: PS3,PS4,PP1_MOD,PM2_SUP,PP3,PP4

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	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, SCV001432641.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (2)
2	not provided	1	not provided	not provided	research	PubMed (2)
3	not provided	1	not provided	not provided	research	PubMed (2)
4	not provided	1	not provided	not provided	research	PubMed (2)
5	not provided	1	not provided	not provided	research	PubMed (2)
6	not provided	1	not provided	not provided	research	PubMed (2)
7	not provided	1	not provided	not provided	research	PubMed (2)
8	not provided	1	not provided	not provided	research	PubMed (2)
9	not provided	1	not provided	not provided	research	PubMed (2)
10	not provided	1	not provided	not provided	research	PubMed (2)
11	not provided	1	not provided	not provided	research	PubMed (2)
12	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
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
7	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
8	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
9	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
10	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
11	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
12	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Johns Hopkins Genomics, Johns Hopkins University, SCV001711949.1

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

Description

This variant (rs121908025) is rare (<0.1%) in a large population database (gnomAD: 8/282882 total alleles, 0.003%, no homozygotes) and has an entry in ClinVar. It has been reported in multiple individuals with familial hypercholesterolemia-1, and is considered a founder mutation in the French-Canadian population. This variant is located in the second type A repeat of the ligand binding domain of the LDLR protein. Functional studies have demonstrated a deleterious effect of p.Trp87Gly on LDL binding and uptake. This variant was also identified in the patient's father, who has a personal history of elevated cholesterol. We consider c.259T>G to be 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 Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV001754778.1

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

Description

The c.259T>G (p.Trp87Gly) variant in the LDLR gene has been reported in multiple individuals with familial hypercholesterolemia (PMID: 2318961, 8054972, 8645371, 9259195, 9104431). It is located in the functionally important second LDLR type A repeat. Functional studies have demonstrated a deleterious effect of the p.Trp87Gly variant on LDL binding (PMID: 2318961, 8645371, 10735631). The variant is observed in gnomAD at a low minor allele frequency (8/282882). Multiple algorithms predicted this change to be deleterious. Therefore, the c.259T>G (p.Trp87Gly) variant in the LDLR gene is classified as 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 ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV001960956.1

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

Description

The NM_000527.5(LDLR):c.259T>G (p.Trp87Gly) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS3, PS4, PP1_Moderate, PM2, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PS3 - Level 1/2 assays: PMID 31578082: Hmz patients' lymphocytes, FACS assays and Heterologous cells (CHO), WB, FACS and CLSM assays - results - lymphocytes: normal cell surface LDLR, 40% LDL-LDLR binding, 35% uptake; CHO: normal (100%) LDLR expression, 20% LDL-LDLR binding, 35% uptake ---- binding and uptake are below 70% of wild-type, so PS3 is Met. PS4 - Variant meets PM2. Variant identified in at least 13 unrelated index cases with Dutch Lipid Clinic score equal or above 6 from different labs. PP1_moderate - variant segregates with FH phenotype in 5 informative meiosis in 2 families from different labs. PM2 - PopMax MAF = 0.00005418 (0.0054%) in european non-finnish exomes (gnomAD v2.1.1). PP3 - REVEL = 0.892. PP4 - Variant meets PM2. Identified in 13 unrelated index cases with Dutch Lipid Clinic score equal or above 6 from different labs.

#	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 Revvity Omics, Revvity, SCV002017127.3

#	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

From Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV002061569.2

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

Description

PS4, PM2_Supporting, PP3, PM1, PS3_Moderate

#	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, SCV004820136.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	PubMed (8)

Description

The c.259T>G (p.Trp87Gly) variant, also known as p.Trp66Gly in LDLR gene that encodes for low density lipoprotein receptor, has been identified in numerous individuals (>100) affected with familial hypercholesterolemia (FH) (PMID:9104431, 2318961, 9259195, 9272705). This variant has also been reported in homozygous status in several individuals (>20) affected with severe FH (PMID: 8098448, 2318961, 9272705). This variant is considered as a founder mutation in the French-Canadian (PMID: 9272705) and Swedish population (PMID: 33955087). Experimental studies using patient derived lymphoblasts from true homozygotes revealed reduced LDLR binding and uptake (PMID: 31578082). Transfection of the mutant, p.Trp87Gly, protein in receptor deficient CHOldlA7 cells also showed significant reduction in LDL binding and uptake (PMID:31578082). Computational prediction tools suggest that the p.Trp87Gly variant may have deleterious effect on the protein function (REVEL score: 0.892). This variant is rare (24/1613912 chromosomes; 0.001487%) in the general population database, gnomAD v4.1.0 and interpreted as pathogenic by several submitters in the ClinVar database including the ClinGen variant curation expert panel (ClinVar ID: 3685). Therefore, the c.259T>G (p.Trp87Gly) variant in LDLR gene is classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	143475	not provided	not provided		4	not provided	not provided	not provided

Last Updated: Jan 13, 2025

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