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

Germline classification:
Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:
Mar 12, 2022
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:
RCV000776469.17

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]

Condition(s)

Name:
Familial hypercholesterolemia
Identifiers:
MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000912019Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Mar 22, 2019) 		germlineclinical testing

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

SCV001580704Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Mar 12, 2022) 		germlineclinical testing

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

Help

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

Disulfide bridges of a cysteine-rich repeat of the LDL receptor ligand-binding domain.

Bieri S, Djordjevic JT, Daly NL, Smith R, Kroon PA.

Biochemistry. 1995 Oct 10;34(40):13059-65.

PubMed [citation]
PMID:
7548065
See all PubMed Citations (10)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000912019.3

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

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.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001580704.4

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

Description

This variant is also known as C240F. For these reasons, this variant has been classified as Pathogenic. 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). Experimental studies have shown that this missense change affects LDLR function (PMID: 10422803). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 3740). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9767373, 10422803, 16542394, 19062533). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121908040, gnomAD 0.002%). This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 261 of the LDLR protein (p.Cys261Phe).

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

Last Updated: Nov 3, 2024