NM_000527.5(LDLR):c.782G>T (p.Cys261Phe) AND Hypercholesterolemia, familial, 1

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Nov 24, 2021
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:: RCV000003938.15

Allele description [Variation Report for NM_000527.5(LDLR):c.782G>T (p.Cys261Phe)]

NM_000527.5(LDLR):c.782G>T (p.Cys261Phe)

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.782G>T (p.Cys261Phe)

Other names:

C240F

HGVS:

NC_000019.10:g.11106652G>T
NG_009060.1:g.22272G>T
NM_000527.5:c.782G>TMANE SELECT
NM_001195798.2:c.782G>T
NM_001195799.2:c.659G>T
NM_001195800.2:c.314-740G>T
NM_001195803.2:c.401G>T
NP_000518.1:p.Cys261Phe
NP_000518.1:p.Cys261Phe
NP_001182727.1:p.Cys261Phe
NP_001182728.1:p.Cys220Phe
NP_001182732.1:p.Cys134Phe
LRG_274t1:c.782G>T
LRG_274:g.22272G>T
LRG_274p1:p.Cys261Phe
NC_000019.9:g.11217328G>T
NM_000527.4:c.782G>T
P01130:p.Cys261Phe
c.782G>T

Protein change:

C134F; CYS240PHE

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000647; UniProtKB: P01130#VAR_013953; OMIM: 606945.0059; dbSNP: rs121908040

NCBI 1000 Genomes Browser:

rs121908040

Molecular consequence:

NM_001195800.2:c.314-740G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.782G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.782G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.659G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.401G>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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000024103	OMIM	no assertion criteria provided	Pathogenic (May 1, 1999)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000294970	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 10422803, 15199436, 16542394 Citation Link,
SCV000607500	Fundacion Hipercolesterolemia Familiar - SAFEHEART	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 1, 2016)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 10422803
SCV000839987	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 12, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002764456	New York Genome Center	criteria provided, single submitter (NYGC Assertion Criteria 2020)	Pathogenic (Nov 24, 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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	4	not provided	not provided	4	not provided	literature only, clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, research

Citations

PubMed

Application of molecular genetics for diagnosing familial hypercholesterolemia in Norway: results from a family-based screening program.

Leren TP, Manshaus T, Skovholt U, Skodje T, Nossen IE, Teie C, Sørensen S, Bakken KS.

Semin Vasc Med. 2004 Feb;4(1):75-85. Review.

PubMed [citation]

PMID:: 15199436

Molecular genetic analysis of 1053 Danish individuals with clinical signs of familial hypercholesterolemia.

Brusgaard K, Jordan P, Hansen H, Hansen AB, Hørder M.

Clin Genet. 2006 Mar;69(3):277-83.

PubMed [citation]

PMID:: 16542394

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000024103.2

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

Description

In a 13-year-old girl with severe hypercholesterolemia (FHCL1; 143890), Ekstrom et al. (1999) demonstrated compound heterozygosity for a cys240-to-phe mutation and a tyr167-to-ter mutation (606945.0045) in the LDLR gene. Fibroblasts from the patient showed very low cholesterol esterification rate, LDL uptake, and degradation as compared to normal fibroblasts. Her 2 heterozygous sibs also carried the C240F mutation, but only one of them was hypercholesterolemic. Ekstrom et al. (1999) expressed the C240F mutant in LDLR-deficient CHOldlA7 cells. The transfected cells produced a detectable protein but were unable to mediate uptake or degradation of LDL. The authors concluded that there may be cholesterol-lowering mechanisms that can be activated, perhaps by mutations in known or hitherto unknown genes.

#	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 LDLR-LOVD, British Heart Foundation, SCV000294970.2

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

#	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

From Fundacion Hipercolesterolemia Familiar - SAFEHEART, SCV000607500.1

#	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):0.002471

"Comp Htz (with p.(Tyr188*)) patients' fibroblasts; Heterologous cells (CHO), 125I-LDL assays"

PubMed [ID: 10422803]

#	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 Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV000839987.1

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

Description

This c.782G>T (p.Cys261Phe) variant has previously been detected in several patients with familial hypercholesterolemia [legacy: 240 in PMID 9767373, 16542394]. The variant was also detected in a 13 y/o female, compound heterozygous for this variant and a loss of function variant [PMID 10422803]. Two siblings carried the same c.782G>T (p.Cys261Phe) heterozygous variant with only one clinically presenting hypercholesterolemia. In vitro assays showed that although the cells produced a detectable protein, cells expressing the mutant protein were unable to mediate uptake and degradation of LDL [PMID 10422803]. This variant has been reported in only one heterozygous individual from the ExAC database (http://exac.broadinstitute.org/variant/19-11217328-G-T). This variant is conserved in mammals and while not clinically validated, computer-based algorithms (SIFT and Polyphen-2) predict this p.Cys261Phe change to be deleterious. This variant is thus 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 New York Genome Center, SCV002764456.1

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

Description

The heterozygous c.782G>T variant identified in LDLR has previously been reported in the literature [PMIDs: 9767373, 10422803, 16542394,24507775, 31447099, 33740630] and in ClinVar [ClinVar ID: 3740] in individuals with familial hypercholesterolemia. The variant has been observed in four alleles with no homozygotes in the population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common variant in the populations represented in those databases. The predicted p.(Cys261Phe) variant (previously reported as p.(Cys240Phe)) resides in the exon 5 of this 18-exon gene and is located within one of the cysteine-rich LDL-receptor class A repeat domains, which contains six disulphide-bound cysteines that are critical for protein structure and stability [PMID:7603991]. In LDL receptors, the class A domains form the binding site for LDL and calcium. In vitro functional studies demonstrated delayed processing of the LDLreceptor [PMID: 10422803]. In silico prediction algorithms are in favor of damaging effect of the variant on the encoded transcript (CADD v1.6= 29.9; REVEL= 0.974). Based on available evidence this heterozygous c.782G>T p.(Cys261Phe) missense variant identified in LDLR is reported as Pathogenic.

#	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

Last Updated: Nov 3, 2024

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