NM_000527.5(LDLR):c.782G>T (p.Cys261Phe) AND Familial hypercholesterolemia 1

Clinical significance:Likely pathogenic (Last evaluated: Apr 12, 2017)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000003938.6

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_000527.4:c.782G>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
  • 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_000527.4:c.782G>T - missense variant - [Sequence Ontology: SO:0001583]
  • 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]

Condition(s)

Name:
Familial hypercholesterolemia 1 (FHCL1)
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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000024103OMIMno assertion criteria providedPathogenic
(May 1, 1999)
germlineliterature only

PubMed (1)
[See all records that cite this PMID]

SCV000294970LDLR-LOVD, British Heart Foundationcriteria provided, single submitter
Likely pathogenic
(Mar 25, 2016)
germlineliterature only

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV000607500Fundacion Hipercolesterolemia Familiar - SAFEHEARTcriteria provided, single submitter
Likely pathogenic
(Mar 1, 2016)
germlineresearch

PubMed (2)
[See all records that cite these PMIDs]

SCV000839987Human Genome Sequencing Center Clinical Lab, Baylor College of Medicinecriteria provided, single submitter
Likely pathogenic
(Apr 12, 2017)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes3not providednot provided3not providedliterature only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, research
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedliterature only PubMed (3)
2not provided1not providednot providedliterature only PubMed (3)
3not provided1not providednot providedliterature only PubMed (3)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot provided1not providednot providednot provided
2germlineyes1not providednot provided1not providednot providednot provided
3germlineyes1not providednot provided1not providednot providednot provided

From Fundacion Hipercolesterolemia Familiar - SAFEHEART, SCV000607500.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearch PubMed (2)
2not providednot providednot providednot providedresearch PubMed (2)

Description

%MAF(ExAC):0.002471

"Comp Htz (with p.(Tyr188*)) patients' fibroblasts; Heterologous cells (CHO), 125I-LDL assays"
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided
2germlineunknownnot providednot providednot providednot providednot providednot providednot provided

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 7, 2021

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