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

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Mar 14, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000776469.3

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 (FH)
Identifiers:
MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000912019Color Health, Inccriteria provided, single submitter
Likely pathogenic
(Mar 22, 2019)
germlineclinical testing

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

SCV001580704Invitaecriteria provided, single submitter
Pathogenic
(Mar 14, 2020)
germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

Description

This missense variant (also known as p.Cys240Phe in the mature protein) is located in the sixth LDLR type A repeat of the ligand binding domain of the LDLR protein. This variant changes one of the functionally critical cysteine residues that form intra-repeat disulfide bonds in the ligand binding domain (PMID: 15952897). Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. An experimental study has demonstrated that the variant protein shows delayed processing and accumulates as a precursor protein in the cells, resulting in defective LDL uptake and degradation (PMID: 10422803). Computational splicing tools suggest that this variant may not impact the RNA splicing. This variant has been reported in individuals with hypercholesterolemia in Sweden and Russia in compound heterozygosity with another deleterious variant in the LDLR gene (PMID: 10422803, 19062533). This variant has been identified in 10/121250 chromosomes by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic.

SCV000912019

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

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]
PMID:
9767373
See all PubMed Citations (10)

Details of each submission

From Color Health, Inc, SCV000912019.2

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

From Invitae, SCV001580704.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

This sequence change replaces cysteine with phenylalanine at codon 261 of the LDLR protein (p.Cys261Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant is present in population databases (rs121908040, ExAC 0.004%). This variant has been observed in individual(s) with familial hypercholesterolemia (PMID: 9767373, 19062533, 16542394, 10422803). It has also been observed to segregate with disease in related individuals. This variant is also known as C240F in the literature. ClinVar contains an entry for this variant (Variation ID: 3740). This variant has been reported to affect LDLR protein function (PMID: 10422803). This variant affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Jul 7, 2021

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