NM_000527.5(LDLR):c.769C>T (p.Arg257Trp) AND Familial hypercholesterolemia 1

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(2);Pathogenic(1);Uncertain significance(4) (Last evaluated: Mar 3, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
8 submissions [Details]
Record status:
current
Accession:
RCV000237953.9

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_000527.4:c.769C>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
  • 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_000527.4:c.769C>T - missense variant - [Sequence Ontology: SO:0001583]
  • 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:
1

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
SCV000294964LDLR-LOVD, British Heart Foundationcriteria provided, single submitter
Likely benign
(Mar 25, 2016)
germlineliterature only

PubMed (6)
[See all records that cite these PMIDs]

Citation Link,

SCV000503232Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foixcriteria provided, single submitter
Likely benign
(Dec 16, 2016)
germlineclinical testing

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

SCV000583738U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lillecriteria provided, single submitter
Pathogenic
(Mar 30, 2017)
germlineclinical testing

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

SCV000588517Laboratory of Genetics and Molecular Cardiology, University of São Paulo - HipercolBrasilcriteria provided, single submitter
Uncertain significance
(Mar 1, 2016)
germlineresearch

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

SCV000606221Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrumno assertion criteria providedPathogenicgermlineresearch

SCV000607499Fundacion Hipercolesterolemia Familiar - SAFEHEARTcriteria provided, single submitter
Uncertain significance
(Mar 1, 2016)
germlineresearch

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

SCV000782953Robarts Research Institute,Western Universitycriteria provided, single submitter
Uncertain significance
(Jan 2, 2018)
germlineclinical testing

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

SCV001432577Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbiacriteria provided, single submitter
Uncertain significance
(Mar 3, 2019)
germlineresearch

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

Description

ACMG Guidelines: Pathogenic (ii)

SCV000583738

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes101not provided2607not providedclinical testing, literature only, research
not providedgermlineunknownnot providednot providednot providednot providednot providedresearch

Citations

PubMed

Identification of recurrent and novel mutations in the LDL receptor gene in German patients with familial hypercholesterolemia.

Nauck MS, Köster W, Dörfer K, Eckes J, Scharnagl H, Gierens H, Nissen H, Nauck MA, Wieland H, März W.

Hum Mutat. 2001 Aug;18(2):165-6.

PubMed [citation]
PMID:
11462246

Molecular basis of familial hypercholesterolemia in Brazil: Identification of seven novel LDLR gene mutations.

Salazar LA, Hirata MH, Cavalli SA, Nakandakare ER, Forti N, Diament J, Giannini SD, Bertolami MC, Hirata RD.

Hum Mutat. 2002 Apr;19(4):462-3.

PubMed [citation]
PMID:
11933210
See all PubMed Citations (9)

Details of each submission

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedliterature only PubMed (6)
2not provided1not providednot providedliterature only PubMed (6)
3not provided1not providednot providedliterature only PubMed (6)
4not provided1not providednot providedliterature only PubMed (6)
5not provided1not providednot providedliterature only PubMed (6)
6not provided1not providednot providedliterature only PubMed (6)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot provided1not providednot providednot provided
2germlineyes1not providednot provided1not providednot providednot provided
3germlineyes1not providednot provided1not providednot providednot provided
4germlineyes1not providednot provided1not providednot providednot provided
5germlineyes1not providednot provided1not providednot providednot provided
6germlineyes1not providednot provided1not providednot providednot 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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testing PubMed (1)

Description

subjects mutated among 2600 FH index cases screened = 2 / in association with c.1765G>A, p.Asp589Asn / Software predictions: Benign

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes2600not providednot provided2not providednot providednot provided

From U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, SCV000583738.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)

Description

Dutch Lipid Clinic Scoring : Definite FH

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not provided1not provided

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

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

Description

%MAF(ExAC):0.007414

"Assay description:Heterologous cells (CHO), FACS assays"
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided
2germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum, SCV000606221.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearchnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Fundacion Hipercolesterolemia Familiar - SAFEHEART, SCV000607499.1

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

Description

%MAF(ExAC):0.007414

"Heterologous cells (CHO), FACS assays"
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided
2germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Robarts Research Institute,Western University, SCV000782953.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia, SCV001432577.1

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

Last Updated: Nov 6, 2021

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