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

Clinical significance:Likely pathogenic (Last evaluated: Feb 13, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:

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

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

LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000527.5(LDLR):c.782G>T (p.Cys261Phe)
Other names:
  • 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
LDLR-LOVD, British Heart Foundation: LDLR_000647; UniProtKB: P01130#VAR_013953; OMIM: 606945.0059; dbSNP: rs121908040
NCBI 1000 Genomes Browser:
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]


Homozygous familial hypercholesterolemia
Familial hypercholesterolemia - homozygous
MONDO: MONDO:0018328; MedGen: C0342881

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000966935Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Likely pathogenic
(Feb 13, 2018)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot provided11not providednot providednot providedclinical testing



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]

Mutations in the low-density lipoprotein receptor gene in Swedish familial hypercholesterolaemia patients: clinical expression and treatment response.

Ekström U, Abrahamson M, Wallmark A, Florén CH, Nilsson-Ehle P.

Eur J Clin Invest. 1998 Sep;28(9):740-7.

PubMed [citation]
See all PubMed Citations (6)

Details of each submission

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000966935.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (6)


The p.Cys261Phe variant in LDLR (also described as p.Cys240Phe in the literature ), has been reported in at least 5 individuals with familial hypercholesterolemi a (FH) in the heterozygous state (Brusgaard 2006, Ekstrom 1999, Ekstrom 1998, Le ren 2004), and in 1 individual with homozygous FH who were compound heterozygote for this variant and a second pathogenic variant in LDLR, where it segregated w ith disease in 2 relatives in one family (Ekstrom 1999). This variant has also b een reported in Clinvar (Variation ID# 3740). In vitro functional studies provid e some evidence that the p.Cys261Phe variant may impact receptor uptake and degr adation (Ekstrom 1999). This variant has been identified in 2/111718 European ch romosomes by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitu te.org; dbSNP rs121908040). This frequency is low enough to be consistent with t he frequency of FH in the general population. Computational prediction tools and conservation analysis suggest that the p.Cys261Phe variant may impact the prote in. In summary, although additional studies are required to fully establish its clinical significance, the p.Cys261Phe variant is likely pathogenic. ACMG/AMP Cr iteria applied (Richards 2015): PM2, PM3, PS4_Moderate, PP3, PS3_Supporting.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided1not provided1not provided

Last Updated: Jul 7, 2021

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